Aztreonam derivatives and uses thereof

ABSTRACT

Disclosed herein are aztreonam derivatives, therapeutic methods of using the aztreonam derivatives, particularly in combination with β-lactamase inhibitors, and pharmaceutical compositions thereof. The aztreonam derivatives can be administered orally to provide orally bioavailable aztreonam.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 62/566,909 filed on Oct. 2, 2017, which isincorporated by reference in its entirety.

FIELD

The present disclosure relates to aztreonam derivatives andpharmaceutical compositions thereof and the use of the aztreonamderivatives to treat bacterial infections. The aztreonam derivatives canbe administered orally to provide orally bioavailable aztreonam.

BACKGROUND

Aztreonam is a monobactam antibiotic used primarily to treat gramnegative bacteria. Aztreonam has poor oral bioavailability and thereforeis administered intravenously, intramuscularly or by inhalation.

SUMMARY

According to the present invention, compounds have the structure ofFormula (1):

wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which each R¹ is bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₈ heterocycloalkyl,substituted C₅₋₆ aryl, and substituted C₅₋₆ heteroaryl, wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

R⁷ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl.

According to the present invention, pharmaceutical compositions comprisea compound according to the present invention and a pharmaceuticallyacceptable vehicle.

According to the present invention, methods of treating a bacterialinfection in a patient comprise administering to a patient in need ofsuch treatment a therapeutically effective amount of a compoundaccording to the present invention.

According to the present invention, methods of treating a bacterialinfection in a patient comprise administering to a patient in need ofsuch treatment a therapeutically effective amount of a pharmaceuticalcomposition according to the present invention.

According to the present invention, methods of synthesizing a derivativeof aztreonam comprise: reacting3-amino-2-tert-butoxycarbonylamino-butyric acid benzyl ester and achlorosulfonyloxy ester in the presence of a base to provide thecorresponding((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxyester; hydrogenating the((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxyester to provide the corresponding(2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoicacid ester; and cyclizing the(2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoicacid ester in the presence of a cyclization agent to provide thecorresponding 3-lactam.

According to the present invention, methods of synthesizing a derivativeof aztreonam comprise: reacting tert-butyl(2S,3R)-3-amino-2-(((benzyloxy)carbonyl)-amino)butanoate and achlorosulfonyloxy ester in the presence of a base to provide thecorresponding tert-butyl(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoateester; and cyclizing the tert-butyl(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoateester in the presence of a cyclization agent to provide thecorresponding 3-lactam.

Reference is now made to certain compounds and methods. The disclosedembodiments are not intended to be limiting of the claims. To thecontrary, the claims are intended to cover all alternatives,modifications, and equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Those skilled in the art will understand that the drawings describedherein are for illustration purposes only. The drawings are not intendedto limit the scope of the present disclosure.

FIG. 1 shows certain steps in synthesizing aztreonam derivativesprovided by the present disclosure. The steps correspond to thosedisclosed in Examples 20-24.

FIG. 2 shows certain steps in synthesizing aztreonam derivativesprovided by the present disclosure. The steps correspond to thosedisclosed in Examples 30-34.

FIG. 3 shows certain steps in synthesizing aztreonam derivativesprovided by the present disclosure. The steps correspond to thosedisclosed in Examples 2 and 27.

DETAILED DESCRIPTION

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is attached through the carbon atom.

“Alkyl” refers to a saturated or unsaturated, branched, orstraight-chain, monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkene,or alkyne. Examples of alkyl groups include methyl; ethyls such asethanyl, ethenyl, and ethynyl; propyls such as propan-1-yl, propan-2-yl,prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, but-1-en-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl,but-3-yn-1-yl, etc.; and the like. The term “alkyl” includes groupshaving any degree or level of saturation, i.e., groups havingexclusively carbon-carbon single bonds, groups having one or morecarbon-carbon double bonds, groups having one or more carbon-carbontriple bonds, and groups having combinations of carbon-carbon single,double, and triple bonds. Where a specific level of saturation isintended, the terms alkanyl, alkenyl, and alkynyl are used. An alkylgroup can be C₁₋₆ alkyl, C₁₋₅ alkyl, C₁₋₄ alkyl, C₁₋₃ alkyl, ethyl ormethyl.

“Alkoxy” refers to a radical —OR where R is alkyl as defined herein.Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.An alkoxy group can be C₁₋₆ alkoxy, C₁₋₅ alkoxy, C₁₋₄ alkoxy, C₁₋₃alkoxy, ethoxy or methoxy.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings,for example, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene. Aryl encompassesmultiple ring systems having at least one carbocyclic aromatic ringfused to at least one carbocyclic aromatic ring, cycloalkyl ring, orheterocycloalkyl ring. For example, aryl includes a phenyl ring fused toa 5- to 7-membered heterocycloalkyl ring containing one or moreheteroatoms selected from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the radical carbon atom may be at the carbocyclic aromatic ring or atthe heterocycloalkyl ring. Examples of aryl groups include groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene, and the like. An aryl group can be C₆₋₁₀ aryl, C₆₋₉aryl, C₆₋₈ aryl, or phenyl. Aryl, however, does not encompass or overlapin any way with heteroaryl, separately defined herein.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom is replaced with an aryl group.Examples of arylalkyl groups include benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl, or arylalkynyl is used. An arylalkyl group canbe C₇₋₁₆ arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is C₁₋₆ and the aryl moiety is C₆₋₁₀. An arylalkyl groupcan be C₇₋₁₆ arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety ofthe arylalkyl group is C₁₋₆ and the aryl moiety is C₆₋₁₀. An arylalkylgroup can be C₇₋₉ arylalkyl, wherein the alkyl moiety is C₁₋₃ alkyl andthe aryl moiety is phenyl. An arylalkyl group can be C₇₋₁₆ arylalkyl,C₇₋₁₄ arylalkyl, C₇₋₁₂ arylalkyl, C₇₋₁₀ arylalkyl, C₇₋₈ arylalkyl, orbenzyl.

“Bioavailability” refers to the rate and amount of a drug that reachesthe systemic circulation of a patient following administration of thedrug or prodrug thereof to the patient and can be determined byevaluating, for example, the plasma or blood concentration-versus-timeprofile for a drug. Parameters useful in characterizing a plasma orblood concentration-versus-time curve include the area under the curve(AUC), the time to maximum concentration (T_(max)), and the maximum drugconcentration (C_(max)), where C_(max) is the maximum concentration of adrug in the plasma or blood of a patient following administration of adose of the drug or form of drug to the patient, and T_(max) is the timeto the maximum concentration (C_(max)) of a drug in the plasma or bloodof a patient following administration of a dose of the drug or form ofdrug to the patient.

“Oral bioavailability” (F %) refers to the fraction of an oraladministered drug that reaches systemic circulation. Oralbioavailability is a product of fraction absorbed, fraction escapinggut-wall elimination, and fraction escaping hepatic elimination; and thefactors that influence bioavailability can be divided intophysiological, physicochemical, and biopharmaceutical factors.

“Compounds” and moieties disclosed herein include any specific compoundswithin the disclosed formula. Compounds may be identified either bychemical structure and/or by chemical name. Compounds are named usingthe ChemBioDraw Ultra 14.0.0.117 (CambridgeSoft, Cambridge, Mass.)nomenclature program. When the chemical structure and chemical nameconflict, the chemical structure is determinative of the identity of thecompound. The compounds described herein may comprise one or morestereogenic centers and/or double bonds and therefore may exist asstereoisomers such as double-bond isomers (i.e., geometric isomers),enantiomers, diastereomers, or atropisomers. Accordingly, any chemicalstructures within the scope of the specification depicted, in whole orin part, with a relative configuration encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure, or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures may be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled in the art.

Compounds and moieties disclosed herein include optical isomers ofcompounds and moieties, racemates thereof, and other mixtures thereof.In such embodiments, the single enantiomers or diastereomers may beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates may be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column with chiral stationaryphases. In addition, compounds include (Z)- and (E)-forms (or cis- andtrans-forms) of compounds with double bonds either as single geometricisomers or mixtures thereof.

Compounds and moieties may also exist in several tautomeric formsincluding the enol form, the keto form, and mixtures thereof.Accordingly, the chemical structures depicted herein encompass allpossible tautomeric forms of the illustrated compounds. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms. Certain compounds may exist in multiple crystalline,co-crystalline, or amorphous forms. Compounds include pharmaceuticallyacceptable salts thereof, or pharmaceutically acceptable solvates of thefree acid form of any of the foregoing, as well as crystalline forms ofany of the foregoing

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylradical. A cycloalkyl group can be C₃₋₆ cycloalkyl, C₃₋₅ cycloalkyl,C₅₋₆ cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. A cycloalkylcan be selected from cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

“Cycloalkylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom is replaced with a cycloalkylgroup as defined herein. Where specific alkyl moieties are intended, thenomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl isused. A cycloalkylalkyl group can be C₄₋₃₀ cycloalkylalkyl, e.g., thealkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group isC₁₋₁₀ and the cycloalkyl moiety of the cycloalkylalkyl moiety is C₃₋₂₀.A cycloalkylalkyl group can be C₄₋₂₀ cycloalkylalkyl, e.g., the alkanyl,alkenyl, or alkynyl moiety of the cycloalkylalkyl group is C₁₋₈ and thecycloalkyl moiety of the cycloalkylalkyl group is C₃₋₁₂. Acycloalkylalkyl can be C₄₋₉ cycloalkylalkyl, wherein the alkyl moiety ofthe cycloalkylalkyl group is C₁₋₃ alkyl, and the cycloalkyl moiety ofthe cycloalkylalkyl group is C₃₋₆ cycloalkyl. A cycloalkylalkyl groupcan be C₄₋₁₂ cycloalkylalkyl, C₄₋₁₀ cycloalkylalkyl, C₄₋₈cycloalkylalkyl, and C₄₋₆ cycloalkylalkyl. A cycloalkylalkyl group canbe cyclopropylmethyl (—CH₂-cyclo-C₃H₅), cyclopentylmethyl(—CH₂-cyclo-C₅H₉), or cyclohexylmethyl (—CH₂-cyclo-C₆H₁₁). Acycloalkylalkyl group can be cyclopropylethenyl (—CH═CH-cyclo-C₃H₅),cyclopentylethynyl (—C≡C-cyclo-C₅H₉), or the like.

“Cycloalkylheteroalkyl” by itself or as part of another substituentrefers to a heteroalkyl group in which one or more of the carbon atoms(and certain associated hydrogen atoms) of an alkyl group areindependently replaced with the same or different heteroatomic group orgroups and in which one of the hydrogen atoms bonded to a carbon atom isreplaced with a cycloalkyl group. Where specific alkyl moieties areintended, the nomenclature cycloalkylheteroalkanyl,cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl is used. In acycloalkylheteroalkyl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group is —O— or —NH—.

“Cycloalkyloxy” refers to a radical —OR where R is cycloalkyl as definedherein. Examples of cycloalkyloxy groups include cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. A cycloalkyloxy groupcan be C₃₋₆ cycloalkyloxy, C₃₋₅ cycloalkyloxy, C₅₋₆ cycloalkyloxy,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Drug” as defined under 21 U.S.C. § 321(g)(l) means “(A) articlesrecognized in the official United States Pharmacopoeia, officialHomeopathic Pharmacopoeia of the United States, or official NationalFormulary, or any supplement to any of them; and (B) articles intendedfor use in the diagnosis, cure, mitigation, treatment, or prevention ofdisease in man or other animals; and (C) articles (other than food)intended to affect the structure or any function of the body of man orother animals . . . ”.

“Fluoroalkyl” refers to an alkyl group as defined herein in which one ormore of the hydrogen atoms is replaced with a fluoro. A fluoroalkylgroup can be C₁₋₆ fluoroalkyl, C₁₋₅ fluoroalkyl, C₁₋₄ fluoroalkyl, orC₁₋₃ fluoroalkyl. A fluoroalkyl group can be pentafluoroethyl (—CF₂CF₃),or trifluoromethyl (—CF₃).

“Fluoroalkoxy” refers to an alkoxy group as defined herein in which oneor more of the hydrogen atoms is replaced with a fluoro. A fluoroalkoxygroup can be C₁₋₆ fluoroalkoxy, C₁₋₅ fluoroalkoxy, C₁₋₄ fluoroalkoxyC₁₋₃, fluoroalkoxy, —OCF₂CF₃ or —OCF₃.

“Halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Heteroalkoxy” refers to an alkoxy group in which one or more of thecarbon atoms are replaced with a heteroatom. A heteroalkoxy group can beC₁₋₆ heteroalkoxy, C₁₋₅ heteroalkoxy, C₁₋₄ heteroalkoxy, or C₁₋₃heteroalkoxy. In a heteroalkoxy, the heteroatomic group can be selectedfrom —O—, —S—, —NH—, —NR— where R is C₁₋₆ alkyl, —SO₂—, and —SO₂—, orthe heteroatomic group can be selected from —O— and —NH—, or theheteroatomic group is —O— and —NH—. A heteroalkoxy group can be C₁₋₆heteroalkoxy, C₁₋₅ heteroalkoxy, C₁₋₄ heteroalkoxy, or C₁₋₃heteroalkoxy.

“Heteroalkyl” by itself or as part of another substituent refer to analkyl group in which one or more of the carbon atoms (and certainassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatomic group or groups. Examples of heteroatomic groupsinclude —O—, —S—, —NH—, —NR—, —O—O—, —S—S—, ═N—N═, —N═N—, —N═N—NR—,—PR—, —P(O)OR—, —P(O)R—, —POR—, —SO—, —SO₂—, and —Sn(R)₂—, where each Ris independently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₆₋₁₂ aryl, substituted C₆₋₁₂ aryl, C₇₋₁₈ arylalkyl, substitutedC₇₋₁₈ arylalkyl, C₃₋₇ cycloalkyl, substituted C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, substituted C₃₋₇ heterocycloalkyl, C₁₋₆ heteroalkyl,substituted C₁₋₆ heteroalkyl, C₆₋₁₂ heteroaryl, substituted C₆₋₁₂heteroaryl, C₇₋₁₈ heteroarylalkyl, and substituted C₇₋₁₈heteroarylalkyl. Each R can be independently selected from hydrogen andC₁₋₃ alkyl. Reference to, for example, a C₁₋₆ heteroalkyl, means a C₁₋₆alkyl group in which at least one of the carbon atoms (and certainassociated hydrogen atoms) is replaced with a heteroatom. For example,C₁₋₆ heteroalkyl includes groups having five carbon atoms and oneheteroatom, groups having four carbon atoms and two heteroatoms, etc. Ina heteroalkyl, the heteroatomic group can be selected from —O—, —S—,—NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group can be —O— or—NH—. A heteroalkyl group can be C₁₋₆ heteroalkyl, C₁₋₅ heteroalkyl, orC₁₋₄ heteroalkyl, or C₁₋₃ heteroalkyl.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system.Heteroaryl encompasses multiple ring systems having at least oneheteroaromatic ring fused to at least one other ring, which may bearomatic or non-aromatic. For example, heteroaryl encompasses bicyclicrings in which one ring is heteroaromatic and the second ring is aheterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systemswherein only one of the rings contains one or more heteroatoms, theradical carbon may be at the aromatic ring or at the heterocycloalkylring. When the total number of N, S, and O atoms in the heteroaryl groupexceeds one, the heteroatoms may or may not be adjacent to one another.The total number of heteroatoms in the heteroaryl group is not more thantwo. In a heteroaryl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group can be —O— or—NH—. A heteroaryl group can be selected from C₅₋₁₀ heteroaryl, C₅₋₉heteroaryl, C₅₋₈ heteroaryl, C₅₋₇ heteroaryl, C₅₋₆ heteroaryl, C₅heteroaryl or C₆ heteroaryl.

Examples of heteroaryl groups include groups derived from acridine,arsindole, carbazole, α-carboline, chromane, chromene, cinnoline, furan,imidazole, indazole, indole, indoline, indolizine, isobenzofuran,isochromene, isoindole, isoindoline, isoquinoline, isothiazole,isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,thiazolidine, and oxazolidine. A heteroaryl groups can be derived, forexample, from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole, or pyrazine. For example, aheteroaryl can be C₅ heteroaryl and can be selected from furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl. Aheteroaryl can be C₆ heteroaryl, and can be selected from pyridinyl,pyrazinyl, pyrimidinyl, and pyridazinyl.

“Heteroarylalkyl” refers to an arylalkyl group in which one of thecarbon atoms (and certain associated hydrogen atoms) is replaced with aheteroatom. A heteroarylalkyl group can be C₆₋₁₆ heteroarylalkyl, C₆₋₁₄heteroarylalkyl, C₆₋₁₂ heteroarylalkyl, C₆₋₁₀ heteroarylalkyl, C₆₋₈heteroarylalkyl, or C₇ heteroarylalkyl, or C₆ heteroarylalkyl. In aheteroarylalkyl, the heteroatomic group can be selected from —O—, —S—,—NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group can be —O— or—NH—.

“Heterocycloalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and certain associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom; or to a parent aromaticring system in which one or more carbon atoms (and certain associatedhydrogen atoms) are independently replaced with the same or differentheteroatom such that the ring system violates the Hückel-rule. Examplesof heteroatoms to replace the carbon atom(s) include N, P, O, S, and Si.Examples of heterocycloalkyl groups include groups derived fromepoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, and quinuclidine. Aheterocycloalkyl can be C₅ heterocycloalkyl and is selected frompyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl,oxazolidinyl, thiazolidinyl, doxolanyl, and dithiolanyl. Aheterocycloalkyl can be C₆ heterocycloalkyl and can be selected frompiperidinyl, tetrahydropyranyl, piperizinyl, oxazinyl, dithianyl, anddioxanyl. A heterocycloalkyl group can be C₃₋₆ heterocycloalkyl, C₃₋₅heterocycloalkyl, C₅₋₆ heterocycloalkyl, C₅ heterocycloalkyl or C₆heterocycloalkyl. In a heterocycloalkyl, the heteroatomic group can beselected from —O—, —S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or theheteroatomic group can be selected from —O— and —NH—, or theheteroatomic group can be —O— or —NH—.

“Heterocycloalkylalkyl” refers to a cycloalkylalkyl group in which oneor more carbon atoms (and certain associated hydrogen atoms) of thecycloalkyl ring are independently replaced with the same or differentheteroatom. A heterocycloalkylalkyl can be C₄₋₁₂ heterocycloalkylalkyl,C₄₋₁₀ heterocycloalkylalkyl, C₄₋₈ heterocycloalkylalkyl, C₄₋₆heterocycloalkylalkyl, C₆₋₇ heterocycloalkylalkyl, or C₆heterocycloalkylalkyl or C₇ heterocycloalkylalkyl. In aheterocycloalkylalkyl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group can be —O— or—NH—.

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a cyclic conjugated π (pi) electron systemwith 4n+2 electrons (Hückel rule). Included within the definition of“parent aromatic ring system” are fused ring systems in which one ormore of the rings are aromatic and one or more of the rings aresaturated or unsaturated, such as, for example, fluorene, indane,indene, phenalene, etc. Examples of parent aromatic ring systems includeaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like.

“Hydrates” refers to incorporation of water into to the crystal latticeof a compound described herein, in stoichiometric proportions, resultingin the formation of an adduct. Methods of making hydrates include, butare not limited to, storage in an atmosphere containing water vapor,dosage forms that include water, or routine pharmaceutical processingsteps such as, for example, crystallization (i.e., from water or mixedaqueous solvents), lyophilization, wet granulation, aqueous filmcoating, or spray drying. Hydrates may also be formed, under certaincircumstances, from crystalline solvates upon exposure to water vapor,or upon suspension of the anhydrous material in water. Hydrates may alsocrystallize in more than one form resulting in hydrate polymorphism.

“Metabolic intermediate” refers to a compound that is formed in vivo bymetabolism of a parent compound and that further undergoes reaction invivo to release an active agent. Compounds of Formula (1) are protectedsulfonate nucleophile prodrugs of aztreonam that are metabolized in vivoto provide the corresponding metabolic intermediates. Metabolicintermediates undergo nucleophilic cyclization to release aztreonam andone or more reaction products. It is desirable that the reactionproducts or metabolites thereof not be toxic.

“Neopentyl” refers to a radical in which a methylene carbon is bonded toa carbon atom, which is bonded to three non-hydrogen substituents.Examples of non-hydrogen substituents include carbon, oxygen, nitrogen,and sulfur. Each of the three non-hydrogen substituents can be carbon.Two of the three non-hydrogen substituents can be carbon, and the thirdnon-hydrogen substituent can be selected from oxygen and nitrogen. Aneopentyl group can have the structure:

where each R¹ can be defined as for Formula (1).

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Examples ofparent aromatic ring systems include aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, and trinaphthalene.

“Parent heteroaromatic ring system” refers to an aromatic ring system inwhich one or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom in such away as to maintain the continuous π-electron system characteristic ofaromatic systems and a number of π-electrons corresponding to the Hückelrule (4n+2). Examples of heteroatoms to replace the carbon atoms includeN, P, O, S, and Si, etc. Specifically included within the definition of“parent heteroaromatic ring systems” are fused ring systems in which oneor more of the rings are aromatic and one or more of the rings aresaturated or unsaturated, such as, for example, arsindole, benzodioxan,benzofuran, chromane, chromene, indole, indoline, xanthene, etc.Examples of parent heteroaromatic ring systems include arsindole,carbazole, 3-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, andthiazolidine, oxazolidine.

“Patient” refers to a mammal, for example, a human.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids andone or more protonable functional groups such as primary, secondary, ortertiary amines within the parent compound. Examples of suitableinorganic acids include hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. A salt can be formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like. A salt can be formed when one or more acidic protons presentin the parent compound are replaced by a metal ion, e.g., an alkalimetal ion, an alkaline earth ion, or an aluminum ion, or combinationsthereof; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, and the like. Apharmaceutically acceptable salt can be the hydrochloride salt. Apharmaceutically acceptable salt can be the sodium salt. In compoundshaving two or more ionizable groups, a pharmaceutically acceptable saltcan comprise one or more counterions, such as a bi-salt, for example, adihydrochloride salt.

The term “pharmaceutically acceptable salt” includes hydrates and othersolvates, as well as salts in crystalline or non-crystalline form. Wherea particular pharmaceutically acceptable salt is disclosed, it isunderstood that the particular salt (e.g., a hydrochloride salt) is anexample of a salt, and that other salts may be formed using techniquesknown to one of skill in the art. Additionally, one of skill in the artwould be able to convert the pharmaceutically acceptable salt to thecorresponding compound, free base and/or free acid, using techniquesgenerally known in the art.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient andwhich does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Pharmaceutical composition” refers to a compound of Formula (1) or apharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable vehicle, with which the compound of Formula(1) or a pharmaceutically acceptable salt thereof is administered to apatient. Pharmaceutically acceptable vehicles are known in the art.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by administeringa compound provided by the present disclosure in a preventative fashion.The application of a therapeutic agent for preventing or prevention of adisease of disorder is known as ‘prophylaxis.’ Compounds provided by thepresent disclosure can provide superior prophylaxis because of lowerlong-term side effects over long time periods.

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently, although not necessarily, pharmacologically inactive untilconverted to the parent drug. Prodrugs may be obtained by bonding apromoiety (defined herein) typically via a functional group, to a drug.For example, referring to compounds of Formula (1), promoieties bondedto the drug aztreonam, via the sulfate group aztreonam of Compounds ofFormula (1) are prodrugs of aztreonam that can be metabolized within apatient's body to release aztreonam.

“Promoiety” refers to a group bonded to a drug, typically to afunctional group of the drug, via bond(s) that are cleavable underspecified conditions of use. The bond(s) between the drug and promoietymay be cleaved by enzymatic or non-enzymatic means. Under the conditionsof use, for example following administration to a patient, the bond(s)between the drug and promoiety may be cleaved to release the parentdrug. The cleavage of the promoiety may proceed spontaneously, such asvia a hydrolysis reaction, or it may be catalyzed or induced by anotheragent, such as by an enzyme, by light, by acid, or by a change of orexposure to a physical or environmental parameter, such as a change oftemperature, pH, etc. The agent may be endogenous to the conditions ofuse, such as an enzyme present in the systemic circulation of a patientto which the prodrug is administered or the acidic conditions of thestomach or the agent may be supplied exogenously. For example, for acompound of Formula (1), a promoiety has the structure:

where R¹, R², and R³ can be defined as for Formula (1).

“Single bond” as in the expression “R² is selected from a single bond”refers to a moiety in which R² and two of the bonds to R² correspond toa single bond. For example, in a moiety having the structure—C(R¹)₂—R²-R³, where R² is a single bond, —R²— corresponds to a singlebond (—), and the moiety has the structure —C(R′)₂—R³.

“Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical arts,which are known to be innocuous to a patient, such as water or ethanol.A molecular complex of a compound or moiety of a compound and a solventcan be stabilized by non-covalent intra-molecular forces such as, forexample, electrostatic forces, van der Waals forces, or hydrogen bonds.The term “hydrate” refers to a solvate in which the one or more solventmolecules is water.

“Solvates” refers to incorporation of solvents into to the crystallattice of a compound described herein, in stoichiometric proportions,resulting in the formation of an adduct. Methods of making solvatesinclude, for example, storage in an atmosphere containing a solvent,dosage forms that include the solvent, or routine pharmaceuticalprocessing steps such as, for example, crystallization (i.e., fromsolvent or mixed solvents) vapor diffusion. Solvates may also be formed,under certain circumstances, from other crystalline solvates or hydratesupon exposure to the solvent or upon suspension material in solvent.Solvates may crystallize in more than one form resulting in solvatepolymorphism.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s). Eachsubstituent can be independently selected from deuterio, halogen, —OH,—CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and—CONR₂; wherein each R is independently selected from hydrogen and C₁₋₆alkyl. Each substituent can be independently selected from deuterio,halogen, —NH₂, —OH, C₁₋₃ alkoxy, and C₁₋₃ alkyl, trifluoromethoxy, andtrifluoromethyl. Each substituent can be independently selected fromdeuterio, —OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, andtrifluoromethoxy. Each substituent can be selected from deuterio, C₁₋₃alkyl, ═O, C₁₋₃ alkyl, C₁₋₃ alkoxy, and phenyl. Each substituent can beselected from deuterio, —OH, —NH₂, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

“Sustained release” refers to release of a compound from a dosage formof a pharmaceutical composition at a rate effective to achieve atherapeutic or prophylactic concentration of the compound or activemetabolite thereof, in the systemic circulation of a patient over aprolonged period of time relative to that achieved by administration ofan immediate release formulation of the same compound by the same routeof administration. In some embodiments, release of a compound occursover a time period of at least about 4 hours, such as at least about 8hours, at least about 12 hours, at least about 16 hours, at least about20 hours, and in some embodiments, at least about 24 hours.

“Treating” or “treatment” of a disease refers to arresting orameliorating a disease or at least one of the clinical symptoms of adisease or disorder, reducing the risk of acquiring a disease or atleast one of the clinical symptoms of a disease, reducing thedevelopment of a disease or at least one of the clinical symptoms of thedisease or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter or manifestation that may or may not bediscernible to the patient. “Treating” or “treatment” also refers todelaying the onset of the disease or delaying the onset of at least oneor more symptoms thereof in a patient who may be exposed to orpredisposed to a disease or disorder even though that patient does notyet experience or display symptoms of the disease.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a patient for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease or symptom thereof. The “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, severity of the disease and/orsymptoms of the disease or disorder, the age, weight, and/or health ofthe patient to be treated, and the judgment of the prescribingphysician. An appropriate amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

“Vehicle” refers to a diluent, excipient or carrier with which acompound is administered to a patient. A vehicle can be apharmaceutically acceptable vehicle. Pharmaceutically acceptablevehicles are known in the art.

Reference is now made in detail to certain embodiments of compounds,compositions, and methods. The disclosed embodiments are not intended tobe limiting of the claims. To the contrary, the claims are intended tocover all alternatives, modifications, and equivalents.

Aztreonam is a monobactam antibiotic used to treat infections causedprimarily by gram-negative bacteria. Aztreonam has poor oralbioavailability. Compounds provided by the present disclosure areN-sulfonate ester prodrugs of aztreonam. The aztreonam N-sulfonate esterprodrugs exhibit enhanced oral bioavailability compared to aztreonam. Inthe aztreonam prodrugs a nucleophilic moiety is positioned proximate thesulfonyl group. In vivo, the nucleophilic moiety reacts to releaseaztreonam in the systemic circulation. Aztreonam,(2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid), has the structure:

Compounds provided by the present disclosure include compounds ofFormula (1):

wherein,

each R¹ can be independently selected from C₁₋₆ alkyl, or each R¹ andthe geminal carbon atom to which each R¹ is bonded forms a C₃₋₆cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆cycloalkyl ring, or a substituted C₃₋₆ heterocycloalkyl ring;

R² can be selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl,

R³ can be selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, and substituted C₅₋₆ heteroaryl, wherein,

-   -   R⁴ can be selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl,        C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl,        C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ can be selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ can be selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl

In compounds of Formula (1), the compounds can have the structure ofFormula (2):

wherein each R¹, R², R³, and R⁷ are defined as for Formula (1).

In compounds of Formula (1), each substituent can independently beselected from deuterio, —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy,C₁₋₆ alkyl, —COOR, —NR₂, and —CONR₂; wherein each R can be independentlyselected from hydrogen and C₁₋₆ alkyl, such has methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, or iso-butyl.

In compounds of Formula (1), a substituent group can be a nucleophilicgroup. Nucleophilic groups are functional group having a reactive pairof electrons and having the ability of forming a chemical bond bydonating electrons. Examples of suitable nucleophilic groups includeesters, carboxylates, sulfonates, substituted or unsubstituted amines,alcohols (hydroxyl), thiols, sulfides, hydroxylamines, and imines. Otherexamples of suitable nucleophilic groups include —OH, —CF₃, —O—CF₃,—NO₂, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴,—NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴,—O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴),where each R⁴ can be independently selected from hydrogen, C₁₋₆ alkyl,C₁₋₆ heteroalkyl, C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀cycloalkylalkyl, C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₆₋₈heteroaryl, C₅₋₁₀ arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₆alkyl, substituted C₁₋₆ heteroalkyl, substituted C₅₋₈ cycloalkyl,substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀ cycloalkylalkyl,substituted C₅₋₁₀ heterocycloalkylalkyl, substituted C₆₋₈ aryl,substituted C₆₋₈ heteroaryl, substituted C₅₋₁₀ arylalkyl, andsubstituted C₅₋₁₀ heteroarylalkyl.

In compounds of Formula (1), each substituent can independently beselected from —OH, —CF₃, —O—CF₃, —NO₂, —O—C(O)—R⁴, —S—C(O)—R⁴,—NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴,—C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—R⁴, —O—(O)—S—R⁴, —O—C(O)—NH—R⁴,—S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), wherein each R⁴ can be selectedfrom hydrogen, C₁₋₈ alkyl, and C₁₋₈ heteroalkyl.

In compounds of Formula (1), R⁷ can be hydrogen.

In compounds of Formula (1), R⁷ can be C₁₋₃ alkyl, such as methyl,ethyl, n-propyl, or iso-propyl.

In compounds of Formula (1), each of R⁵ and R⁶ can be hydrogen.

In compounds of Formula (1), R⁷ can be hydrogen; and R⁵ and R⁶ can behydrogen.

In compounds of Formula (1), R⁷ can be C₁₋₃ alkyl, such as methyl,ethyl, n-propyl, or iso-propyl; and each of R⁵ and R⁶ can be hydrogen.

In compounds of Formula (1) and (2), R⁷ can be selected from hydrogen,C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂ cycloalkylalkyl, C₂₋₆ heteroalkyl,C₅₋₈ heterocycloalkyl, C₆₋₁₂ heterocycloalkylalkyl.

In compounds of Formula (1) and (2), R⁷ can be selected from hydrogen,C₁₋₆ alkyl, C₅₋₈ cycloalkyl, and C₆₋₁₂ cycloalkylalkyl.

In compounds of Formula (1) and (2), R⁷ can be selected from hydrogen,ethyl, tert-butyl, hexyl, —(CH₂)₂—O—CH₃, and

(4-(yl-methyl)-5-methyl-1,3-dioxol-2-one).

In compounds of Formula (1) and (2), R⁷ can be selected from hydrogenand C₁₋₆ alkyl.

In compounds of Formula (1), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of Formula (1), the compounds can have the structure ofFormula (3):

wherein each R¹, R², and R³ are defined as for Formula (1).

In compounds of Formula (1), R⁵ can be C₂₋₆ heteroalkyl comprising aterminal amine group, and R⁶ can be hydrogen. For example, R⁵ can be—O—(CH₂)₂—NH₂, —CH₂—O—CH₂—NH₂, or —(CH₂)₂—O—CH₂—NH₂, —CH₂—O—(CH₂)₂—NH₂.

In compounds of Formula (1) and (2), R⁷ can be hydrogen, R⁵ can be—O—(CH₂)₂—NH₂, and R⁶ can be hydrogen.

In compounds of Formula (1) and (2), R⁵ can be C₄₋₆ heterocycloalkylcomprising at least one —NH— moiety, and R⁶ can be hydrogen. Forexample, R⁵ can be 2-yl-piperidine, 3-yl-piperidine, or 4-yl-piperidine.

In compounds of Formula (1) and (2), R⁷ can be hydrogen, R⁵ can be4-yl-piperidine, and R⁶ can be hydrogen.

In compounds of Formula (1)-(3), each R¹ can independently be C₁₋₆alkyl.

In compounds of Formula (1)-(3), each R¹ can independently be methyl,ethyl, or n-propyl.

In compounds of Formula (1)-(3), each R¹ can be the same and can bemethyl, ethyl, or n-propyl.

In compounds of Formula (1)-(3), each R¹ can be methyl.

In compounds of Formula (1)-(3), each R¹ together with the geminalcarbon atom to which each R¹ can be bonded can form a C₃₋₆ cycloalkylring or a substituted C₃₋₆ cycloalkyl ring.

In compounds of Formula (1)-(3), each R¹ together with the geminalcarbon atom to which each R¹ is bonded can form a C₃₋₆ cycloalkyl ring.For example, each R¹ together with the geminal carbon atom to which eachR¹ is bonded can form a cyclopropyl ring, a cyclobutyl ring, acyclopentyl ring, or a cyclohexyl ring.

In compounds of Formula (1)-(3), each R¹ together with the geminalcarbon atom to which each R¹ is bonded can form a C₃₋₆ heterocycloalkylring or a substituted C₃₋₆ heterocycloalkyl ring.

In compounds of Formula (1)-(3), R² can be selected from a single bond,C₁₋₂ alkanediyl, and substituted C₁₋₂ alkanediyl.

In compounds of Formula (1)-(3), R² can be a single bond.

In compounds of Formula (1)-(3), R² can be a single bond; and R³ can beC₁₋₆ alkyl.

In compounds of Formula (1)-(3), R² can be selected from C₁₋₂ alkanediyland substituted C₁₋₂ alkanediyl.

In compounds of Formula (1)-(3), R² can be methanediyl, ethanediyl,substituted methanediyl, or substituted ethanediyl.

In compounds of Formula (1)-(3), R² can be substituted C₁₋₂ alkanediylwhere the substituent group can be selected from —OH, —CN, —CF₃, —OCF₃,═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and —CONR₂; wherein eachR can be independently selected from hydrogen and C₁₋₆ alkyl.

In compounds of Formula (1)-(3), R² can be substituted C₁₋₂ alkanediylwhere the substituent group can be a nucleophilic group. For example, R²can be substituted C₁₋₂ alkanediyl where the substituent group can beselected from —OH, —CF₃, —O—CF₃, —NO₂, —O—C(O)—R⁴, —S—C(O)—R⁴,—NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴,—C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴,—S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), where each R⁴ is defined as forFormula (1), or each R⁴ can be selected from hydrogen and C₁₋₈ alkyl.

In compounds of Formula (1)-(3), R² can be substituted C₁₋₂ alkanediylwhere the substituent group can be selected from —OH, —O—C(O)—R⁴,—S—C(O)—R⁴, —NH—C(O)—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —S—S—R⁴,—S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), substituted C₅₋₆ aryl, —NHR⁴, and—CH(—NH₂)(—R⁴), where R⁴ is defined as for Formula (1), or each R⁴ canbe selected from hydrogen and C₁₋₈ alkyl.

In compounds of Formula (1)-(3), where R² can be substituted C₁₋₆alkanediyl, substituted C₁₋₆ heteroalkanediyl, or substituted C₅₋₆arenediyl, the stereochemistry of the carbon atom to which thesubstituent group is bonded can be of the (S) configuration.

In compounds of Formula (1)-(3), where R² can be substituted C₁₋₆alkanediyl, substituted C₁₋₆ heteroalkanediyl, or substituted C₅₋₆arenediyl, the stereochemistry of the carbon atom to which thesubstituent group is bonded can be of the (R) configuration.

In compounds of Formula (1)-(3), R² can be selected from C₅₋₆cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₅₋₆ arenediyl, and C₅₋₆heterocycloalkanediyl.

In compounds of Formula (1)-(3), R² can be cyclopenta-1,3-diene-diyl,substituted cyclopenta-1,3-diene-diyl, benzene-diyl or substitutedbenzene-diyl. For example, R² can be 1,2-benzene-diyl or substituted1,2-benzene-diyl.

In compounds of Formula (1)-(3), R³ can be selected from —O—C(O)—R⁴,—S—C(O)—R⁴, —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴,—C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—(O)—S—R⁴,—O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, and —CH(—NH₂)(—R⁴), where R⁴ isdefined as for Formula (1), or each R⁴ can be selected from hydrogen andC₁₋₈ alkyl.

In compounds of Formula (1)-(3), R³ can be selected from —O—C(O)—R⁴,—C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴, —NH—R⁴, and —CH(—NH₂)(—R⁴);where R⁴ is defined as for Formula (1), or each R⁴ can be selected fromhydrogen and C₁₋₈ alkyl.

In compounds of Formula (1)-(3), R³ can be —C(O)—O—R⁴, where R⁴ isdefined as for Formula (1), or each R⁴ can be selected from hydrogen andC₁₋₈ alkyl.

In compounds of Formula (1)-(3), R⁴ can be selected from hydrogen, C₁₋₃alkyl, C₅₋₆ cycloalkyl, C₅₋₆ heterocycloalkyl, C₅₋₆ aryl, substitutedC₁₋₃ alkyl, substituted C₅₋₆ cycloalkyl, substituted C₅₋₆heterocycloalkyl, and substituted C₅₋₆ aryl.

In compounds of Formula (1)-(3), R⁴ can be selected from methyl, ethyl,phenyl, and benzyl.

In compounds of Formula (1)-(3), R⁴ can be selected from hydrogen andC₁₋₈ alkyl.

In compounds of Formula (1)-(3), R⁴ can be selected from C₁₋₈ alkyl,C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, C₅₋₇ heterocycloalkyl, substitutedC₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl, substituted C₇₋₉ arylalkyl,and substituted C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(3), R⁴ can be selected from C₁₋₈ alkyl,C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(3), R⁴ can be selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl,2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl,cyclohexyl, and 2-pyrrolidinyl.

In compounds of Formula (1)-(3), R³ can be C(O)—O—R⁴; and R⁴ can beselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₇ cycloalkyl, C₅₋₇heterocycloalkyl, C₆ aryl, C₇₋₉ arylalkyl, substituted C₁₋₈ alkyl,substituted C₁₋₈ heteroalkyl, substituted C₅₋₆ cycloalkyl, substitutedC₅₋₆ heterocycloalkyl, substituted C₆ aryl, and C₇₋₉ arylalkyl,

In compounds of Formula (1)-(3), R³ can be C(O)—O—R⁴; and R⁴ can beselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, C₅₋₇heterocycloalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl,substituted C₇₋₉ arylalkyl, and substituted C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(3), R³ can be C(O)—O—R⁴; and R⁴ can beselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇heterocycloalkyl.

In compounds of Formula (1)-(3), R³ can be selected from —O—C(O)—CH₃,—O—C(O)—CH₂—CH₃, —O—C(O)-phenyl, —O—C(O)—CH₂-phenyl, —S—C(O)—CH₃,—S—C(O)—CH₂—CH₃, —S—C(O)— phenyl, —S—C(O)—CH₂-phenyl, —NH—C(O)—CH₃,—NH—C(O)—CH₂—CH₃, —NH—C(O)-phenyl, —NH—C(O)—CH₂-phenyl, —O—C(O)—O—CH₃,—O—C(O)—O—CH₂—CH₃, —O—C(O)—O-phenyl, —O—C(O)—O—CH₂-phenyl,—S—C(O)—O—CH₃, —S—C(O)—O—CH₂—CH₃, —S—C(O)—O-phenyl,—S—C(O)—O—CH₂-phenyl, —NH—C(O)—O—CH₃, —NH—C(O)—O—CH₂—CH₃,—NH—C(O)—O-phenyl, —NH—C(O)—O—CH₂-phenyl, —C(O)—O—CH₃, —C(O)—O—CH₂—CH₃,—C(O)—O-phenyl, —C(O)—O—CH₂-phenyl, —C(O)—S—CH₃, —C(O)—S—CH₂—CH₃,—C(O)—S-phenyl, —C(O)—S—CH₂-phenyl, —C(O)—NH—CH₃, —C(O)—NH—CH₂—CH₃,—C(O)—NH-phenyl, —C(O)—NH—CH₂-phenyl, —O—C(O)—O—CH₃, —O—C(O)—O—CH₂—CH₃,—O—C(O)—O-phenyl, —O—C(O)—O—CH₂-phenyl, —O—C(O)—S—CH₃,—O—C(O)—S—CH₂—CH₃, —O—C(O)—S-phenyl, —O—C(O)—S—CH₂-phenyl,—O—C(O)—NH—CH₃, —O—C(O)—NH—CH₂—CH₃, —O—C(O)—NH-phenyl,—O—C(O)—NH—CH₂-phenyl, —S—SH, —S—S—CH₃, —S—S—CH₂—CH₃, —S—S-phenyl,—S—S—CH₂-phenyl, —SH, —S—CH₃, —S—CH₂—CH₃, —S-phenyl, —S—CH₂-phenyl,—NH₂, —NH—CH₃, —NH—CH₂—CH₃, —NH-phenyl, —NH—CH₂-phenyl, —CH(—NH₂)(—CH₃),—CH(—NH₂)(—CH₂—CH₃), —CH(—NH₂)(-phenyl), and —CH(—NH₂)(—CH₂-phenyl).

In compounds of Formula (1)-(3), R³ can be selected from C₅₋₆cycloalkyl, C₅₋₆ heterocycloalkyl, C₅₋₆ aryl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl, andsubstituted C₅₋₆ aryl, and substituted C₅₋₆ heteroaryl, comprising atleast one nucleophilic group. For example, R³ can have the structure ofFormula (5a) or Formula (5b):

In compounds of Formula (1)-(3), R⁴ can be selected from C₁₋₃ alkyl,C₅₋₆ cycloalkyl, C₅₋₆ heterocycloalkyl, C₅₋₆ aryl, substituted C₁₋₃alkyl, substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,and substituted C₅₋₆ aryl.

In compounds of Formula (1)-(3), each R¹ together with the carbon atomto which each R¹ is bonded form a C₄₋₆ heterocycloalkyl ring comprisingtwo adjacent S atoms or a substituted C₄₋₆ heterocycloalkyl ringcomprising at least one heteroatom selected from O and S, and a ═Osubstituent group bonded to a carbon atom adjacent the at least oneheteroatom.

In compounds of Formula (1)-(3), R² can be a single bond; R³ can be C₁₋₃alkyl; and each R¹ together with the carbon atom to which each R¹ isbonded form a C₄₋₆ heterocycloalkyl ring comprising two adjacent S atomsor a substituted C₄₋₆ heterocycloalkyl ring comprising at least oneheteroatom selected from O and S, and a ═O substituent group bonded to acarbon atom adjacent the heteroatom.

In compounds of Formula (1)-(3), each R¹ together with the carbon atomto which they are bonded can from a C₄-, C₅-, or C₆-heterocycloalkylgroup. The heterocycloalkyl group can have two adjacent sulfur atoms. Incompounds of Formula (1)-(3) in each R¹ together with the carbon atom towhich they are bonded can from a C₄-, C₅-, or C₆-heterocycloalkyl group,R² can be a single bond and R³ can be C₁₋₆ alkyl, such as C₁₋₄ alkyl,such as methyl or ethyl:

In compounds of Formula (1)-(3), each R¹ together with the carbon atomto which they are bonded can from a substituted C₄-, substituted C₅-, orsubstituted C₆-heterocycloalkyl group. The substituted heterocycloalkylgroup can have a sulfur atom and an adjacent carbonyl (═O) group. Thesubstituted heterocycloalkyl group can have am oxygen atom and anadjacent carbonyl (═O) group.

In compounds of Formula (1)-(3), each R¹ together with the carbon atomto which they are bonded can from a substituted C₄-, substituted C₅-, orsubstituted C₆-heterocycloalkyl group, R³ can be a single bond and R⁴can be C₁₋₆ alkyl, such as C₁₋₄ alkyl, such as methyl or ethyl:

In compounds of Formula (1)-(3), R² can be a single bond; R³ can be C₁₋₃alkyl; and each R¹ together with the carbon atom to which each R¹ isbonded can form a C₄₋₆ heterocycloalkyl ring or a substituted C₄₋₆heterocycloalkyl ring.

In compounds of Formula (1)-(3), R² can be a single bond; R³ can be C₁₋₃alkyl; and each R¹ together with the carbon atom to which each R¹ isbonded can form a C₄₋₆ heterocycloalkyl ring comprising two adjacent Satoms or a substituted C₄₋₆ heterocycloalkyl ring comprising at leastone heteroatom selected from O and S, and a ═O substituent group bondedto a carbon atom adjacent the heteroatom.

In compounds of Formula (1)-(3), R² can be a single bond; R³ can be C₁₋₃alkyl; and each R¹ together with the carbon atom to which each R¹ isbonded can form a 1,2-dithiolante ring, a 1,2-dithane ring, athietan-2-one ring, a dihydrothiophen-2(3H)-one ring, atetrahydro-2H-thipyran-2-one ring, an oxetan-2-one ring, adihydrofuran-2(3H)-one ring, or a tetrahydro-2H-pyran-2-one ring.

In compounds of Formula (1)-(3),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴), where R⁴ can be selected fromhydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and2-pyrrolidinyl.

In compounds of Formula (1)-(3),

each R¹ and the geminal carbon to which each R¹ is bonded can form aC₃₋₆ cycloalkyl ring;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴), where R⁴ can be selected fromhydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and2-pyrrolidinyl.

In compounds of Formula (1)-(3),

R² can be a single bond;

R³ be C₁₋₃ alkyl; and

each R¹ together with the carbon atom to which each R¹ is bonded canform a 1,2-dithiolante ring, a 1,2-dithane ring, a thietan-2-one ring, adihydrothiophen-2(3H)-one ring, a tetrahydro-2H-thipyran-2-one ring, anoxetan-2-one ring, a dihydrofuran-2(3H)-one ring, or atetrahydro-2H-pyran-2-one ring.

In compounds of Formula (1)-(3),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴); wherein R⁴ can be selected from C₁₋₈alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(3),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ can be—C(O)—O—R⁴; wherein R⁴ can be selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(3),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴); wherein R⁴ can be selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl,tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl,cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

In compounds of Formula (1)-(3),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be —C(O)—O—R⁴; wherein R⁴ can be selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl,2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl,cyclohexyl, and 2-pyrrolidinyl.

In compounds of Formula (1)-(3),

each R¹ can be methyl;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴;

wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₇₋₁₀alkylarene, and C₅₋₁₀ heteroalkylcycloalkyl.

In compounds of Formula (1)-(3),

each R¹ can be methyl;

R² can be a single bond;

R³ can be —C(O)—O—R⁴; wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₇₋₁₀ alkylarene, and C₅₋₁₀ heteroalkylcycloalkyl; and

each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of Formula (1)-(3), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of Formula (1)-(3), each R¹ can be independently C₁₋₃alkyl; each R² can be a single bond; and each of R⁵, R⁶, and R⁷ can behydrogen.

In compounds of Formula (1)-(3), each R¹ can be independently C₁₋₃alkyl; and each R² can be a single bond.

In compounds of Formula (1)-(3), each R¹ can be independently selectedfrom C₁₋₃ alkyl, or each R¹ together with the geminal carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring, a substituted C₃₋₆cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, or a substituted C₃₋₆heterocycloalkyl ring;

R² can be a single bond;

R³ can be —C(O)—O—R⁴; and

R⁴ can be selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl,C₅₋₇ heterocycloalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₇₋₉ arylalkyl, and substituted C₅₋₇heterocycloalkyl.

In compounds of Formula (1)-(3),

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be selected from single bond, methane-diyl, and ethane-diyl; and

R³ can be selected from —C(O)—O—R⁴ and —S—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆heterocycloalkyl, and substituted C₄₋₁₀ heterocycloalkylalkyl.

In compounds of Formula (1)-(3),

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, where R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In compounds of Formula (1)-(3),

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be —(CH₂)₂—; and

R³ can be —C(O)—O—R⁴ wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In compounds of Formula (1)-(3),

each R¹ can be selected from C₁₋₃ alkyl, or each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring;

R² can be —CH₂—; and

R³ can be —S—C(O)—R⁴, wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, substituted C₄₋₁₀heterocycloalkylalkyl.

In compounds of Formula (1)-(3),

each R¹ together with the carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a C₃₋₆ cycloalkylring, or a C₃₋₆ heterocycloalkyl ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

In compounds of Formula (1)-(3), each R¹ can be independently selectedfrom C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be selected from —O—C(O)—R⁴ and —C(O)—O—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl and substituted phenyl.

In compounds of Formula (1)-(3),

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be a single bond;

R³ can be —CH═C(R⁴)₂, wherein each R⁴ can be —C(O)—O—R⁸, or each R⁴together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring; and

each R⁸ can be C₁₋₄ alkyl.

In compounds of Formula (1)-(3),

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be substituted phenyl, wherein the one or more substituents canbe independently selected from —CH₂—O—C(O)—R⁴ and —O—C(O)—R⁴, wherein R⁴can be selected from C₁₋₁₀ alkyl and phenyl.

In compounds of Formula (1)-(3), each R¹ can be independently selectedfrom C₁₋₃ alkyl;

R² can be selected from —C(R⁸)₂— and —CH₂—C(R)₂—, wherein each R⁸ can beindependently selected from C₁₋₃ alkyl; and

R³ can be selected from —C(O)—O—R⁴ and —O—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, substituted C₁₋₁₀ alkyl,substituted C₁₋₁₀ heteroalkyl, and4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

In compounds of Formula (1)-(3),

each R¹ together with the carbon atom to which they are bonded form asubstituted C₅₋₆ heterocyclic ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

In compounds of Formula (1),

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

R² is a single bond; and

R³ is —C(O)—O—R⁴, where R⁴ is selected from C₁₋₆ alkyl.

A compound of Formula (1) can be a compound of sub-genus (1A), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be selected from single bond, methane-diyl, and ethane-diyl; and

R³ can be selected from —C(O)—O—R⁴ and —S—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆heterocycloalkyl, and substituted C₄₋₁₀ heterocycloalkylalkyl.

In compounds of subgenus (1A), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1A), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1A), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1A), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1A), R² a single bond.

In compounds of subgenus (1A), R² can be methane-diyl.

In compounds of subgenus (1A), R² can be ethane-diyl.

In compounds of subgenus (1A), R³ can be —C(O)—O—R⁴.

In compounds of subgenus (1A), R³ can be —S—C(O)—R⁴.

In compounds of subgenus (1A), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1A), R⁴ can be C₁₋₁₀ heteroalkyl.

In compounds of subgenus (1A), R⁴ can be C₅₋₁₀ arylalkyl.

In compounds of subgenus (1A), R⁴ can be C₃₋₆ heterocycloalkyl.

In compounds of subgenus (1A), R⁴ can be substituted C₄₋₁₀heterocycloalkylalkyl.

A compound of Formula (1) can be a compound of sub-genus (1B), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, where R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In compounds of subgenus (1B), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1B), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1B), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1B), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1B), R⁴ can be selected from C₁₋₇ alkyl, C₁₋₁₀heteroalkyl wherein the one or more heteroatoms can be oxygen, —CH₂—C₄₋₆cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl wherein theone or more heteroatoms can be oxygen, and —CH₂—C₃₋₆ substitutedheterocycloalkyl, and —(CH₂)₂—C₃₋₆ substituted heterocycloalkyl.

In compounds of subgenus (1B), in the substituted C₃₋₆ heterocycloalkylthe one or more heteroatoms can be oxygen, and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1B), each R¹ can be methyl, or each R¹together with the carbon atom to which they are bonded form a cyclohexylring or a cyclopentyl ring.

In compounds of subgenus (1B), R⁴ can be selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, n-hexyl, n-heptyl, —CH₂—CH₂—O—CH₃,benzyl, 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

In compounds of subgenus (1B),

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be methyl, or each R¹ together with the carbon atom to whichthey are bonded form a cyclohexyl ring or a cyclopentyl ring;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, wherein R⁴ can be selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, n-hexyl, n-heptyl, —CH₂—CH₂—O—CH₃,—CH₂-phenyl (benzyl), 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

A compound of Formula (1) can be a compound of sub-genus (1C), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be —(CH₂)₂—; and

R³ can be —C(O)—O—R⁴ wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In compounds of subgenus (1C), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1C), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1C), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1C), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1C), R⁴ can be selected from C₁₋₇ alkyl, C₁₋₁₀heteroalkyl wherein the one or more heteroatoms can be oxygen, —CH₂—C₄₋₆cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl wherein theone or more heteroatoms can be oxygen, —CH₂—C₃₋₆ substitutedheterocycloalkyl, and —(CH₂)₂—C₃₋₆ substituted heterocycloalkyl.

In compounds of subgenus (1C), in the substituted C₃₋₆ heterocycloalkylthe one or more heteroatoms can be oxygen, and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1C), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1C),

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be methyl;

R² can be —(CH₂)₂—; and

R³ can be —C(O)—O—R⁴ wherein R⁴ can be selected from n-hexyl andn-heptyl.

A compound of Formula (1) can be a compound of sub-genus (1D), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be selected from C₁₋₃ alkyl, or each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring;

R² can be —CH₂—; and

R³ can be —S—C(O)—R⁴, wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, substituted C₄₋₁₀heterocycloalkylalkyl.

In compounds of subgenus (1D), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1D), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1D), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1D), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1D), R⁴ can be selected from C₁₋₇ alkyl, C₁₋₁₀heteroalkyl wherein the one or more heteroatoms can be oxygen, —CH₂—C₄₋₆cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl, C₃-heterocycloalkyl wherein the oneor more heteroatoms can be oxygen, —CH₂—C₃₋₆ substitutedheterocycloalkyl, —(CH₂)₂—C₃₋₆ substituted heterocycloalkyl.

In compounds of subgenus (1D), in the substituted C₃₋₆ heterocycloalkylthe one or more heteroatoms can be oxygen, and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1D), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1D),

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be methyl;

R² can be —CH₂—; and

R³ can be —S—C(O)—R⁴, wherein R⁴ can be methyl.

A compound of Formula (1) can be a compound of sub-genus (1E), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

each R¹ together with the carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a C₃₋₆ cycloalkylring, or a C₃₋₆ heterocycloalkyl ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

In compounds of subgenus (1E), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1E), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1E), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ heterocycloalkyl ring or a C₃₋₆heterocycloalkyl ring;

In compounds of subgenus (1E), the one or more heteroatoms can be oxygenand the one or more substituents can be ═O.

In compounds of subgenus (1E),

each R¹ together with the carbon atom to which they are bonded form adihydrofuran-2(3H)-one ring;

R² can be a single bond; and

R³ can be methyl.

A compound of Formula (1) can be a compound of sub-genus (1F), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be selected from —O—C(O)—R⁴ and —C(O)—O—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl and substituted phenyl.

In compounds of subgenus (1F), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1F), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1F), R² can be a single bond.

In compounds of subgenus (1F), R² can be methanediyl.

In compounds of subgenus (1F), R³ can be —O—C(O)—R⁴.

In compounds of subgenus (1F), R² can be methanediyl; and R³ can be—O—C(O)—R⁴.

In compounds of subgenus (1F), R³ can be —C(O)—O—R⁴.

In compounds of subgenus (1F), R² can be a single bond; and R³ can be—C(O)—O—R⁴.

In compounds of subgenus (1F), R² can be a single bond; R³ can be—C(O)—O—R⁴; and R⁴ can be C₁₋₃ alkyl.

In compounds of subgenus (1F), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1F), R⁴ can be C₁₋₄ alkyl.

In compounds of subgenus (1F), R⁴ can be substituted phenyl.

In compounds of subgenus (1F), R² can be methanediyl; R³ can be—O—C(O)—R⁴; and R⁴ can be substituted phenyl.

In compounds of subgenus (1F), the one or more substituents can beindependently selected from halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In compounds of subgenus (1F), the substituted phenyl can be2,6-substituted phenyl.

In compounds of subgenus (1F), each of the substituents can be selectedfrom C₁₋₃ alkyl and Ca-3 alkoxy.

In compounds of subgenus (1F), the substituted phenyl can be2,5,6-substituted phenyl.

In compounds of subgenus (1F), each of the substituents at the 2 and 6positions can be independently selected from C₁₋₃ alkyl and C₁₋₃ alkoxy;and the substituent at the 5 position can be halogen.

A compound of Formula (1) can be a compound of sub-genus (1G), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be a single bond; and

R³ can be —CH═C(R⁴)₂, wherein each R⁴ can be —C(O)—O—R⁸, or each R⁴together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring; and

each R⁸ can be C₁₋₄ alkyl.

In compounds of subgenus (1G), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1G), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1G), each R⁴ can be —C(O)—O—R⁸.

In compounds of subgenus (1G), each R⁴ can be —C(O)—O—R⁸, or each R⁴together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring.

In compounds of subgenus (1G), in the substituted heterocyclohexyl ring,the one or more heteroatoms can be oxygen.

In compounds of subgenus (1G), in the substituted heterocyclohexyl ring,the one or more substituents can be independently selected from C₁₋₃alkyl and ═O.

In compounds of subgenus (1G), the substituted heterocycloalkyl ring canbe 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione.

A compound of Formula (1) can be a compound of sub-genus (1H), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each of R⁵, R⁶, and R⁷ can be hydrogen;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be substituted phenyl, wherein the one or more substituents canbe independently selected from —CH₂—O—C(O)—R⁴ and —O—C(O)—R⁴, wherein R⁴can be selected from C₁₋₁₀ alkyl and phenyl.

In compounds of subgenus (1H), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1H), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl, and C₁₋₆ heteroalkyl.

In compounds of subgenus (1H), R² can be a single bond.

In compounds of subgenus (1H), R² can be 2-substituted phenyl.

In compounds of subgenus (1H), the one or more substituents can be—CH₂—O—C(O)—R⁴.

In compounds of subgenus (1H), the one or more substituents can be—O—C(O)—R⁴.

In compounds of subgenus (1H), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1H), R⁴ can be selected from methyl, ethyl,iso-propyl, pivalolyl, and phenyl.

A compound of Formula (1) can be a compound of sub-genus (1I), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from —C(R⁸)₂— and —CH₂—C(R)₂—, wherein each R⁸ can beindependently selected from C₁₋₃ alkyl; and

R³ can be selected from —C(O)—O—R⁴ and —O—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, substituted C₁₋₁₀ alkyl,substituted C₁₋₁₀ heteroalkyl, and4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

In compounds of subgenus (1I), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1I), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alkyl and C₁₋₆ heteroalkyl.

In compounds of subgenus (1I), each R¹ can be methyl.

In compounds of subgenus (1I), R² can be —C(R)₂—.

In compounds of subgenus (1I), R² can be —CH₂—C(R)₂—.

In compounds of subgenus (1I), each R⁸ can be methyl.

In compounds of subgenus (1I), each R¹ can be methyl; and each R⁸ can bemethyl.

In compounds of subgenus (1I), R³ can be —C(O)—O—R⁴.

In compounds of subgenus (1I), R³ can be —O—C(O)—R⁴.

A compound of Formula (1) can be a compound of sub-genus (1J), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ together with the carbon atom to which they are bonded form asubstituted C₅-heterocyclic ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

In compounds of subgenus (1J), in the substituted C₅₋₆ heterocyclicring, the one or more heteroatoms can be oxygen; and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1J), each R¹ together with the carbon atom towhich they are bonded form a tetrahydro-2H-pyran-2-one ring.

In compounds of subgenus (1J),

each of R⁵ and R⁶ can be hydrogen;

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from C₂₋₄ alkanediyl; and

R³ can be substituted C₅₋₆ heterocycloalkyl, wherein the one or moreheteroatoms can be independently selected from N and O; and the one ormore substituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1J), each of R⁵, R⁶, and R⁷ can be hydrogen.

In compounds of subgenus (1J), each of R⁵ and R⁶ can be hydrogen; and R⁷can be selected from C₁₋₆ alky, and C₁₋₆ heteroalkyl.

In compounds of subgenus (1J), R³ can have the structure of Formula (5):

wherein R⁹ can be selected from hydrogen, C₁₋₆ alkyl, C₄₋₆ cycloalkyl,C₁₋₆ heteroalkyl, C₄₋₆ heterocycloalkyl, substituted C₁₋₆ alkyl,substituted C₄₋₆ cycloalkyl, substituted C₁₋₆ heteroalkyl, andsubstituted C₄₋₆ heterocycloalkyl.

In compounds of subgenus (1J), R⁹ can be selected from hydrogen and C₁₋₆alkyl such as C₁₋₄ alkyl such as methyl or ethyl.

A compound of Formula (1) can have the structure of Formula (4):

wherein each R¹, R⁴, and R⁷ is defined as for Formula (1).

In compound of Formula (4),

each R¹ can be selected from C₁₋₆ alkyl;

R⁴ can be selected from C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₅₋₆ cycloalkyl,and C₅₋₆ heterocycloalkyl; and

R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

In compounds of Formula (4), each R¹ can be selected from C₁₋₃ alkyl; R⁴can be selected from C₁₋₆ alkyl and C₅₋₆ cycloalkyl; and R⁷ can beselected from hydrogen and C₁₋₆ alkyl.

In compounds of Formula (1), the compound can be selected from:

-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-oxo-3-propoxypropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   methyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   ethyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   propyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   methyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   ethyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   propyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   methyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   ethyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   propyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

In compounds of Formula (1), the compound can be selected from:

-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzoyloxy)-2,2-dimethylpropoxy)    sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-(benzoyloxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(propionyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-((6-(benzyloxy)-6-oxohexanoyl)oxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   6-(4-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-isopropoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(tert-butoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-(oxetan-3-yloxy)-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclopentyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclobutyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

A compound of Formula (1)-(4) can be a solvate, a pharmaceuticallyacceptable salt, or a combination thereof.

In compounds of Formula (1)-(4), a pharmaceutically acceptable salt canbe the hydrochloride salt.

In compounds of Formula (1)-(4), a pharmaceutically acceptable salt canbe the dihydrochloride salt.

A compound of Formula (1)-(4) can be a pharmaceutically acceptable saltof a compound of Formula (1)-(4), a hydrate thereof, or a solvate of anyof the foregoing.

Compounds of Formula (1)-(4) can be synthesized using methods known inthe art. The synthesis of aztreonam is described, for example, in Singhet al., Organic Process Research & Development, 2002, 6, 863-868.Formation of sulfate esters is also well-known in the art as disclosed,for example, in Simpson et al., J. Am. Chem. Soc. 2006, 128, 1605.

The general steps to synthesize a prodrug on an N-sulfonate group, suchas the N-sulfate group of aztreonam is provided as follows.

Referring to FIG. 1, starting with Boc-O-benzyl threonine 1, treatmentwith triflate anhydride followed by reaction with tetrabutyl ammoniumazide provides the corresponding azide intermediate 20.Trimethylphosphine reduction of the azide intermediate 20 produces thecorresponding amino ester 21 in 60% yield. N-sulfonylation of the aminoester 22 with chlorosulfonate provides the corresponding sulfamate 25with a 30% yield. Quantitative hydrogenolysis affords the sulfamate acid23, which undergoes cyclization to the corresponding β-lactam 24 with a54% yield. The steps are disclosed in Examples 20-24.

FIG. 2 shows an alternative route for synthesizing sulfonate esterprodrugs of aztreonam. Starting from the commercially available aminoN-sulfonate, formation of the N-Cbz β-lactam followed by desulfationprovides the corresponding oxazetidine 30. Treatment of the oxazetidine9 with aqueous formic acid affords the crystalline amino acid 31. Inthis case the sulfonylation proceeds from acid 31 to the correspondingto tert-butyl ester. Treatment with a chlorosulfonate as shown in FIG. 1provides acid N-sulfonate ester 33. Cyclization of the sulfonate ester33 gives corresponding β-lactam 34 in a 21% yield. The amine group ofthe lactam 34 can the be deprotected to provide the correspondingoxoazetidine N-sulfonate ester 35. The steps are provided in Examples30-34.

FIG. 3 shows a method for attaching a2-((((2-aminothiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methylpropanoicacid sidechain to the N-sulfonated oxazetidine ring. The steps areprovided in Examples 26-27.(Z)-2-(2-Aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)aceticacid (la) is reacted with tritylchloride in the presence of a base toprovide the corresponding tritylamine 26. The tritylamine 26 is reactedwith the N-sulfonate ester to provide the corresponding3-((((2S,3S)-3-((E)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-(tert-butylamino)thiazol-4-yl)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)ester 25/35 which can be deprotected and then esterified as appropriateto provide the corresponding aztreonam N-sulfonate ester prodrugs.

Compounds of Formula (1) or pharmaceutically acceptable salts thereofmay be incorporated into pharmaceutical compositions to be administeredto a patient by any appropriate route of administration includingintradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, peroral, sublingual, intracerebral,intravaginal, transdermal, rectal, inhalation, or topical.Pharmaceutical compositions provided by the present disclosure can beprovided as oral formulations. Oral formulations may be oral dosageforms.

Pharmaceutical compositions provided by the present disclosure maycomprise a therapeutically-effective amount of a compound of Formula (1)or a pharmaceutically acceptable salt thereof together with a suitableamount of one or more pharmaceutically acceptable vehicles so as toprovide a composition for proper administration to a patient. Suitablepharmaceutical vehicles and methods of preparing pharmaceuticalcompositions are described in the art. Examples of suitablepharmaceutical vehicles are described in the art.

Pharmaceutical compositions comprising a compound may be manufactured bymeans of conventional mixing, dissolving, granulating, levitating,emulsifying, encapsulating, entrapping or lyophilizing processes.Pharmaceutical compositions may be formulated in a suitable manner usingone or more physiologically acceptable carriers, diluents; excipients orauxiliaries, which facilitate processing of compounds into preparationswhich can be used pharmaceutically. Suitable formulation is dependentupon the route of administration chosen.

A compound of Formula (1) may be incorporated into pharmaceuticalcompositions to be administered orally. Oral administration of suchpharmaceutical compositions may result in uptake of the compound ofFormula (1) throughout or in a portion of the gastrointestinal tract andentry into the systemic circulation. Such compositions may be preparedin a manner known in the pharmaceutical art and can comprise a compoundof Formula (1) and at least one pharmaceutically acceptable vehicle.Pharmaceutical compositions may include a therapeutically effectiveamount of a compound of Formula (1) and a suitable amount of apharmaceutically acceptable vehicle, so as to provide an appropriateform for administration to a patient.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered pharmaceutical compositions may contain one or moreoptional agents, for example, sweetening agents such as fructose,aspartame or saccharin, flavoring agents such as peppermint, oil ofwintergreen, or cherry coloring agents and preserving agents, to providea pharmaceutically palatable preparation. Moreover, in tablet or pillforms, the pharmaceutical compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds andpharmaceutical compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral pharmaceutical compositions mayinclude standard vehicles such as mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, etc. Suchvehicles may be of pharmaceutical grade.

For oral liquid preparations, such as suspensions, elixirs andsolutions, can include suitable carriers, excipients, or diluentsinclude water, saline, alkylene glycols (e.g., propylene glycol),polyalkylene glycols (e.g., polyethylene glycol) oils, alcohols,slightly acidic buffers from about pH 4 to about pH 6 (e.g., acetate,citrate, ascorbate from about 5 mM to about 50 mM), etc. Additionally,flavoring agents, preservatives, coloring agents, bile salts,acylcarnitines, and the like may be added.

Compositions comprising a compound of Formula (1) associated with atleast one pharmaceutically acceptable vehicle including excipients,carriers, diluents and/or adjuvants. In forming the compositions, acompound of Formula (1) may be mixed with an excipient, diluted by adiluent or enclosed within a carrier, which can be in the form of acapsule, sachet, paper or other container. When an excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which canact as a vehicle, carrier, or medium for a compound of Formula (1).Thus, compositions may be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,and syrups containing, for example, up to 90 wt % of a compound ofFormula (1) using, for example, soft and hard gelatin capsules, where wt% is based on the total weight of the dosage form.

In preparing a composition, it may be useful to mill a compound ofFormula (1) to provide an appropriate particle size prior to combiningwith other ingredients. The milled particle size of a compound ofFormula (1) may be adjusted depending on the aqueous solubility, and canbe, for example, less than 200 mesh, less than 100 mesh, or less than 40mesh. Examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water, syrup, andmethylcellulose. Compositions may additionally include lubricatingagents such as talc, magnesium stearate, and mineral oil, wettingagents, emulsifying and suspending agents, preserving agents such asmethyl- and propylhydroxy-benzoates, sweetening agents, pH adjusting andbuffering agents, toxicity adjusting agents, flavoring agents, and thelike. The compositions may be formulated so as to provide quick,sustained, or delayed release a compound of Formula (1) after oraladministration to the patient by employing procedures known in the art.

A composition may be formulated in unit dosage form, each dosage formcomprising an equivalent weight of a compound of Formula (1) within arange, for example, from 10 mg to 10 g. A unit dosage form refers to aphysically discrete unit suitable as a unitary dosage for humans andother mammals, each unit containing a predetermined quantity of activematerial calculated to produce an intended therapeutic effect, inassociation with a suitable pharmaceutical excipient, diluent, carrierand/or adjuvant.

For preparing solid compositions such as tablets, a compound of Formula(1) may be mixed with a pharmaceutical excipient, diluent, carrierand/or adjuvant to form a solid pre-formulation composition containing ahomogeneous mixture containing a compound of Formula (1). When referringto these pre-formulation compositions as homogeneous, it is meant that acompound of Formula (1) is dispersed evenly throughout the compositionso that the composition can be readily subdivided into equally effectiveunit dosage forms such as tablets, pills, or capsules. This solidpre-formulation can then be subdivided into unit dosage forms of thetype described herein comprising, for example, an equivalent weight ofaztreonam ranging from about 10 mg to about 10 g.

Tablets or pills comprising a compound of Formula (1) may be coated orotherwise compounded to provide a dosage form affording the advantage ofsustained release. For example, a tablet or pill may comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over and/or enclosing the former. The two components may beseparated by an enteric layer. The enteric layer may serve to resistdisintegration in the stomach and permit the inner component to passintact into the duodenum, or to delay release. A variety of materialsmay be used for such enteric layers or coatings. For example, suchmaterials include a number of polymeric acids and mixtures of polymericacids with such materials as shellac, cetyl alcohol, or celluloseacetate.

Liquid dosage forms in which the compositions a compound of Formula (1)may be incorporated for oral administration can include aqueoussolutions suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

An oral formulation comprising a compound of Formula (1) may bepracticed with a number of different dosage forms, which can be adaptedto provide sustained release of a compound of Formula (1) following oraladministration.

A sustained release oral dosage form can comprise, for example, beadsthat on dissolution or diffusion release the prodrug over an extendedperiod of hours, in certain embodiments, over a period of at least about4 hours, in some embodiments, over a period of at least about 8 hours,over a period of at least about 12 hours, over a period of at leastabout 16 hours, over a period of at least about 20 hours, over a periodof at least about 24 hours, and in certain embodiments, over a period ofmore than about 24 hours. Prodrug-releasing beads may have a centralcomposition or core comprising a compound of Formula (1) and at leastone pharmaceutically acceptable vehicle, and may include an optionallubricant, antioxidant, and/or buffer. Examples of suitabletimed-release beads are known in the art.

Enteric-coated preparations may be used for oral sustained releaseadministration. Coating materials include polymers with a pH-dependentsolubility (i.e., pH-controlled release), polymers with a slow orpH-dependent rate of swelling, dissolution or erosion (i.e.,time-controlled release), polymers that can be degraded by enzymes(i.e., enzyme-controlled release) and polymers that form firm layersthat can be destroyed by an increase in pressure (i.e.,pressure-controlled release).

Drug-releasing lipid matrices or prodrug-releasing waxes may be used fororal sustained release administration.

Dosage forms may comprise a compound of Formula (1) coated on a polymersubstrate. The polymer may be an erodible or a non-erodible polymer.

A dosage form may comprise a compound of Formula (1) loaded into apolymeric matrix that releases the prodrug by diffusion through apolymer, or by flux through pores or by rupture of a polymer matrix.

Osmotic delivery systems are used for oral sustained releaseadministration

Regardless of the specific form of sustained release oral dosage formused, a compound of Formula (1) may be released from a dosage form suchas an orally administered dosage form, over a sufficient period of timeto provide prolonged therapeutic concentrations of a compound of Formula(1) in the blood of a patient enabling administration of the dosage formon only a once or twice per day basis. Following oral administration,dosage forms comprising a compound of Formula (1) can provide atherapeutic or prophylactic concentration of aztreonam in the plasmaand/or blood of a patient for a time period of at least about 4 hours,for at least about 8 hours, for at least about 12 hours, for at leastabout 16 hours, for at least about 20 hours, or for at least about 24hours following oral administration of the dosage form to the patient. Atherapeutically or prophylactically effective concentration of aztreonamin the blood and/or plasma of a patient can depend on a number offactors including, for example, the disease being treated, the severityof the disease, the weight of the patient, the health of the patient,and so forth.

Pharmaceutical compositions provided by the present disclosure comprisea compound of Formula (1) together with a suitable amount of one or morepharmaceutically acceptable vehicles so as to provide a composition forproper administration to a patient. Examples of suitable pharmaceuticalvehicles are known in the art.

Pharmaceutical compositions comprising a compound of Formula (1) may bemanufactured by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Pharmaceutical compositions may be formulated ina conventional manner using one or more physiologically acceptablecarriers, diluents, excipients, or auxiliaries, which facilitateprocessing of compounds of Formula (1) or crystalline form thereof andone or more pharmaceutically acceptable vehicles into formulations thatcan be used pharmaceutically. Proper formulation is dependent upon theroute of administration chosen. In certain embodiments, a pharmaceuticalcomposition comprising a compound of Formula (1) or crystalline formthereof may be formulated for oral administration, and in certainembodiments for sustained release oral administration. Pharmaceuticalcompositions provided by the present disclosure may take the form ofsolutions, suspensions, emulsion, tablets, pills, pellets, capsules,capsules containing liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for administration to a patient.

Pharmaceutical compositions provided by the present disclosure may beformulated in a unit dosage form. A unit dosage form refers to aphysically discrete unit suitable as a unitary dose for patientsundergoing treatment, with each unit containing a predetermined quantityof at least one compound of Formula (1) calculated to produce anintended therapeutic effect. A unit dosage form may be for a singledaily dose, for administration 2 times per day, or one of multiple dailydoses, e.g., 3 or more times per day. When multiple daily doses areused, a unit dosage may be the same or different for each dose. One ormore dosage forms may comprise a dose, which may be administered to apatient at a single point in time or during a time interval.

In certain embodiments, a compound of Formula (1) may be incorporatedinto pharmaceutical compositions to be administered orally. Oraladministration of such pharmaceutical compositions may result in uptakeof a compound of Formula (1) throughout the intestine and entry into thesystemic circulation. Such oral compositions may be prepared in a mannerknown in the pharmaceutical art and comprise at least one compound ofFormula (1) and at least one pharmaceutically acceptable vehicle. Oralpharmaceutical compositions may include a therapeutically effectiveamount of at least one compound of Formula (1) and a suitable amount ofa pharmaceutically acceptable vehicle, so as to provide an appropriateform for administration to a patient.

Pharmaceutical compositions comprising at least one compound of Formula(1) may be formulated for immediate release for parenteraladministration, oral administration, or for any other appropriate routeof administration.

Controlled drug delivery systems may be designed to deliver a drug insuch a way that the drug level is maintained within a therapeuticallyeffective window and effective and safe blood levels are maintained fora period as long as the system continues to deliver the drug at aparticular rate. Controlled drug delivery may produce substantiallyconstant blood levels of a drug over a period of time as compared tofluctuations observed with immediate release dosage forms. For somedrugs, maintaining a constant blood and tissue concentration throughoutthe course of therapy is the most desirable mode of treatment. Immediaterelease of drugs may cause blood levels to peak above the level requiredto elicit a desired response, which may waste the drug and may cause orexacerbate toxic side effects. Controlled drug delivery can result inoptimum therapy, and not only can reduce the frequency of dosing, butmay also reduce the severity of side effects. Examples of controlledrelease dosage forms include dissolution-controlled systems,diffusion-controlled systems, ion exchange resins, osmoticallycontrolled systems, erodable matrix systems, pH independentformulations, gastric retention systems, and the like.

An oral dosage form provided by the present disclosure may be acontrolled release dosage form. Controlled delivery technologies canimprove the absorption of a drug in a particular region or regions ofthe gastrointestinal tract.

The appropriate oral dosage form for a particular pharmaceuticalcomposition provided by the present disclosure may depend, at least inpart, on the gastrointestinal absorption properties of a compound ofFormula (1), the stability of a compound of Formula (1) in thegastrointestinal tract, the pharmacokinetics of a compound of Formula(1), and the intended therapeutic profile. An appropriate controlledrelease oral dosage form may be selected for a particular compound ofFormula (1). For example, gastric retention oral dosage forms may beappropriate for compounds absorbed primarily from the uppergastrointestinal tract, and sustained release oral dosage forms may beappropriate for compounds absorbed primarily from the lowergastrointestinal tract. Certain compounds are absorbed primarily fromthe small intestine. In general, compounds traverse the length of thesmall intestine in about 3 to 5 hours. For compounds that are not easilyabsorbed by the small intestine or that do not dissolve readily, thewindow for active agent absorption in the small intestine may be tooshort to provide a desired therapeutic effect.

Gastric retention dosage forms, i.e., dosage forms that are designed tobe retained in the stomach for a prolonged period of time, may increasethe bioavailability of drugs that are most readily absorbed by the uppergastrointestinal tract. For example, certain compounds of Formula (1)may exhibit limited colonic absorption and be absorbed primarily fromthe upper gastrointestinal tract. Thus, dosage forms that release acompound of Formula (1) in the upper gastrointestinal tract and/orretard transit of the dosage form through the upper gastrointestinaltract will tend to enhance the oral bioavailability of the compound ofFormula (1). The residence time of a conventional dosage form in thestomach is about 1 to about 3 hours. After transiting the stomach, thereis approximately a 3-hour to 5-hour window of bioavailability before thedosage form reaches the colon. However, if the dosage form is retainedin the stomach, the drug may be released before it reaches the smallintestine and will enter the intestine in solution in a state in whichit can be more readily absorbed. Another use of gastric retention dosageforms is to improve the bioavailability of a drug that is unstable tothe basic conditions of the intestine.

Pharmaceutical compositions provided by the present disclosure may bepracticed with dosage forms adapted to provide sustained release of acompound of Formula (1) upon oral administration. Sustained release oraldosage forms may be used to release drugs over a prolonged time periodand are useful when it is desired that a drug or drug form be deliveredto the lower gastrointestinal tract. Sustained release oral dosage formsinclude any oral dosage form that maintains therapeutic concentrationsof a drug in a biological fluid such as the plasma, blood, cerebrospinalfluid, or in a tissue or organ for a prolonged time period. Sustainedrelease oral dosage forms include diffusion-controlled systems such asreservoir devices and matrix devices, dissolution-controlled systems,osmotic systems, and erosion-controlled systems. Sustained release oraldosage forms and methods of preparing the same are well known in theart.

Sustained release oral dosage forms may be in any appropriate form fororal administration, such as, for example, in the form of tablets,pills, or granules. Granules can be filled into capsules, compressedinto tablets, or included in a liquid suspension. Sustained release oraldosage forms may additionally include an exterior coating to provide,for example, acid protection, ease of swallowing, flavor,identification, and the like.

sustained release oral dosage forms may comprise a therapeuticallyeffective amount of a compound of Formula (1) and at least onepharmaceutically acceptable vehicle. In certain embodiments, a sustainedrelease oral dosage form may comprise less than a therapeuticallyeffective amount of a compound of Formula (1) and a pharmaceuticallyeffective vehicle. Multiple sustained release oral dosage forms, eachdosage form comprising less than a therapeutically effective amount of acompound of Formula (1) may be administered at a single time or over aperiod of time to provide a therapeutically effective dose or regimenfor treating a disease in a patient. In certain embodiments, a sustainedrelease oral dosage form comprises more than one compound of Formula(1).

Sustained release oral dosage forms provided by the present disclosurecan release a compound of Formula (1) from the dosage form to facilitatethe ability of the compound of Formula (1) to be absorbed from anappropriate region of the gastrointestinal tract, for example, in thesmall intestine or in the colon. Sustained release oral dosage forms mayrelease a compound of Formula (1) from the dosage form over a period ofat least about 4 hours, at least about 8 hours, at least about 12 hours,at least about 16 hours, at least about 20 hours, and in certainembodiments, at least about 24 hours. In certain embodiments, sustainedrelease oral dosage forms may release a compound of Formula (1) from thedosage form in a delivery pattern corresponding to about 0 wt % to about20 wt % in about 0 to about 4 hours; about 20 wt % to about 50 wt % inabout 0 to about 8 hours; about 55 wt % to about 85 wt % in about 0 toabout 14 hours; and about 80 wt % to about 100 wt % in about 0 to about24 hours; where wt % refers to the percent of the total weight of thecompound in the dosage form. Sustained release oral dosage forms mayrelease a compound of Formula (1) from the dosage form in a deliverypattern corresponding to about 0 wt % to about 20 wt % in about 0 toabout 4 hours; about 20 wt % to about 50 wt % in about 0 to about 8hours; about 55 wt % to about 85 wt % in about 0 to about 14 hours; andabout 80 wt % to about 100 wt % in about 0 to about 20 hours. Sustainedrelease oral dosage forms may release a compound of Formula (1) from thedosage form in a delivery pattern corresponding to about 0 wt % to about20 wt % in about 0 to about 2 hours; about 20 wt % to about 50 wt % inabout 0 to about 4 hours; about 55 wt % to about 85 wt % in about 0 toabout 7 hours; and about 80 wt % to about 100 wt % in about 0 to about 8hours.

Sustained release oral dosage forms comprising a compound of Formula (1)may provide a concentration of the corresponding drug in the plasma,blood, cerebrospinal fluid, or tissue of a patient over time, followingoral administration to the patient. The concentration profile of thedrug may exhibit an AUC that is proportional to the dose of thecorresponding compound of Formula (1).

Regardless of the specific type of controlled release oral dosage formused, a compound of Formula (1) may be released from an orallyadministered dosage form over a sufficient period of time to provideprolonged therapeutic concentrations of the compound of Formula (1) inthe plasma and/or blood of a patient. Following oral administration, adosage form comprising a compound of Formula (1) may provide atherapeutically effective concentration of the corresponding drug in theplasma and/or blood of a patient for a continuous time period of atleast about 4 hours, of at least about 8 hours, for at least about 12hours, for at least about 16 hours, and in certain embodiments, for atleast about 20 hours following oral administration of the dosage form tothe patient. The continuous time periods during which a therapeuticallyeffective concentration of the drug is maintained may be the same ordifferent. The continuous period of time during which a therapeuticallyeffective plasma concentration of the drug is maintained may beginshortly after oral administration or following a time interval.

An appropriate dosage of a compound of Formula (1) or pharmaceuticalcomposition comprising a compound of Formula (1) may be determinedaccording to any one of several well-established protocols. For example,animal studies such as studies using mice, rats, dogs, and/or monkeysmay be used to determine an appropriate dose of a pharmaceuticalcompound. Results from animal studies may be extrapolated to determinedoses for use in other species, such as for example, humans.

Pharmaceutical compositions provided by the present disclosure may beadministered for therapeutic or prophylactic treatments. A therapeuticamount is an amount sufficient to remedy a disease state or symptoms, orotherwise prevent, hinder, retard, or reverse the progression of diseaseor any other undesirable symptoms in any way whatsoever. In prophylacticapplications, pharmaceutical compositions or the present disclosure maybe administered to a patient susceptible to or otherwise at risk of aparticular disease or infection. Hence, a prophylactically effectiveamount is an amount sufficient to prevent, hinder or retard a diseasestate or its symptoms.

An appropriate dosage of the pharmaceutical composition may bedetermined according to any one of several well-established protocols.For example, animal studies, such as studies using mice or rats, may beused to determine an appropriate dose of a pharmaceutical compound.Results based on animal studies can be extrapolated to determine dosesfor use in other species, such as for example, humans. For example, theefficacy of a compound of Formula (1) and compositions thereof fortreating an infectious disease may be assessed using animal and humanmodels of infectious disease and clinical studies. A compound of Formula(1) or pharmaceutical compositions thereof may be administered assustained release systems, and in certain embodiments, as orallyadministered sustained release systems. A compound of Formula (1) may bedelivered by oral sustained release administration. A compound ofFormula (1) or pharmaceutical compositions thereof may be orallyadministered, for example, twice per day, once per day, or at intervalsgreater than once per day.

The amount of a compound of Formula (1) that will be effective in thetreatment of a cancer will depend, at least in part, on the nature ofthe disease, and may be determined by standard clinical techniques knownin the art. In addition, in vitro or in vivo assays may be employed tohelp identify optimal dosing ranges. Dosing regimens and dosingintervals may also be determined by methods known to those skilled inthe art. The amount of compound of Formula (1) administered may dependon, among other factors, the patient being treated, the weight of thepatient, the severity of the disease, the route of administration, andthe judgment of the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. Initial doses may also beestimated from in vivo data, e.g., animal models, using techniques thatare known in the art. Such information may be used to more accuratelydetermine useful doses in humans. One having ordinary skill in the artmay optimize administration to humans based on animal data.

A dose of compound of Formula (1) and appropriate dosing intervals maybe selected to maintain a sustained therapeutically effectiveconcentration of the compound of Formula (1) in the blood of a patient,and in certain embodiments, without exceeding a minimum adverseconcentration.

In certain embodiments an administered dose is less than a toxic dose.Toxicity of the compositions described herein may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., by determining the LD₅₀ (the dose lethal to 50% of thepopulation) or the LD₁₀₀ (the dose lethal to 100% of the population).The dose ratio between toxic and therapeutic effect is the therapeuticindex. In certain embodiments, an aztreonam prodrug may exhibit a hightherapeutic index. The data obtained from these cell culture assays andanimal studies may be used in formulating a dosage range that is nottoxic for use in humans. A dose of an aztreonam prodrug provided by thepresent disclosure may be within a range of circulating concentrationsin for example the blood, plasma, or central nervous system, thatinclude the effective dose and that exhibits little or no toxicity. Adose may vary within this range depending upon the dosage form employedand the route of administration utilized. In certain embodiments, anescalating dose may be administered.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered once per day, twice per day, and in certain embodiments atintervals of more than once per day. Dosing may be provided alone or incombination with other drugs and may continue as long as required foreffective treatment of the disease. Dosing may also be undertaken usingcontinuous or semi-continuous administration over a period of time.Dosing includes administering a pharmaceutical composition to a mammal,such as a human, in a fed or fasted state.

A pharmaceutical composition may be administered in a single dosage formor in multiple dosage forms or as a continuous or an accumulated doseover a period of time. When multiple dosage forms are used the amount ofcompound of Formula (1) contained within each of the multiple dosageforms may be the same or different.

Suitable daily dosage ranges for administration may range from about 2μg to about 20 mg of a compound of Formula (1) per kilogram body weight.

Suitable daily dosage ranges for administration may range from about 1μg to about 50 mg of a compound of Formula (1) per square meter (m²) ofbody surface.

A compound of Formula (1) may be administered to treat an infectiousdisease in a patient in an amount from about 1 mg to about 2,000 mg perday, from about 100 μg to about 1,500 mg per day, from about 20 μg toabout 1,000 mg per day, or in any other appropriate daily dose.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered to treat an infectious disease in a patient and provide atherapeutically effective concentration of a compound of Formula (1) inthe blood or plasma of the patient. A therapeutically effectiveconcentration of a compound of Formula (1) in the blood or plasma of apatient can be, for example, from about 1 μg/mL to about 60 μg/mL, fromabout 2 μg/mL to about 50 μg/mL, from about 5 μg/mL to about 40 μg/mL,from about 5 μg/mL to about 20 μg/mL, or from about 5 μg/mL to about 10μg/mL. A therapeutically effective concentration of a compound ofFormula (1) in the blood or plasma of a patient can be, for example, atleast about 2 μg/mL, at least about 5 μg/mL, at least about 10 μg/mL, atleast about 15 μg/mL, at least about 25 μg/mL, or at least about 30μg/mL. A therapeutically effective concentration of a compound ofFormula (1) in the blood or plasma of a patient can be less than anamount that causes unacceptable adverse effects including adverseeffects to homeostasis. A therapeutically effective concentration of acompound of Formula (1) in the blood or plasma of a patient can be anamount sufficient to restore and/or maintain homeostasis in the patient.For example, following administration of a therapeutically effectivedose of a compound of Formula (1), a therapeutically effective amount ofaztreonam can be maintained for greater than 1 hour, greater than 2hours, greater than 3 hours, greater than 4 hours, greater than 5 hours,greater than 6 hours, greater than 7 hours, or greater than 8 hours. Forexample, following administration of a therapeutically effective dose ofa compound of Formula (1), a therapeutically effective amount ofaztreonam can be maintained, for example, from 1 hour to 10 hours, from2 hours to 8 hours, from 2 hours to 6 hours, or from 2 hours to 4 hours.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered to treat an infectious disease in a patient so as toprovide a therapeutically effective concentration of a compound ofFormula (1) in the blood or plasma of a patient for an extended periodof time such as, for example, for at least about 4 hours, for at leastabout 6 hours, for at least about 8 hours, for at least about 10 hours,and in certain embodiments, for at least about 12 hours.

The amount of a compound of Formula (1) administered may vary during atreatment regimen.

Pharmaceutical compositions provided by the present disclosure mayfurther comprise one or more pharmaceutically active compounds inaddition to a compound of Formula (1). Such compounds may be provided totreat the infectious disease being treated with the compound of Formula(1) or to treat a disease, disorder, or condition other than theinfectious disease being treated with the compound of Formula (1).

A compound of Formula (1) may be used in combination with at least oneother therapeutic agent. A compound of Formula (1) may be administeredto a patient together with another compound for treating infectiousdisease in the patient. The at least one other therapeutic agent may bea second compound encompassed by compounds of Formula (1). A compound ofFormula (1) and the at least one other therapeutic agent may actadditively or, and in certain embodiments, synergistically. The at leastone additional therapeutic agent may be included in the samepharmaceutical composition or vehicle comprising the compound of Formula(1) or may be in a separate pharmaceutical composition or vehicle.Accordingly, methods provided by the present disclosure further include,in addition to administering a compound of Formula (1), administeringone or more therapeutic agents effective for treating an infectiousdisease or a different disease, disorder or condition than theinfectious disease. Methods provided by the present disclosure includeadministration of a compound of Formula (1) and one or more othertherapeutic agents provided that the combined administration does notinhibit the therapeutic efficacy of a compound of Formula (1) and/ordoes not produce adverse combination effects.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered concurrently with the administration of another therapeuticagent, which may be part of the same pharmaceutical composition as, orin a different pharmaceutical composition than that comprising acompound of Formula (1). A compound of Formula (1) may be administeredprior or subsequent to administration of another therapeutic agent. Incertain embodiments of combination therapy, the combination therapy maycomprise alternating between administering a compound of Formula (1) anda composition comprising another therapeutic agent, e.g., to minimizeadverse drug effects associated with a particular drug and/or to enhancetreatment efficacy. When a compound of Formula (1) is administeredconcurrently with another therapeutic agent that potentially may producean adverse drug effect including, for example, toxicity, the othertherapeutic agent may be administered at a dose that falls below thethreshold at which the adverse drug reaction is elicited.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered with one or more substances to enhance, modulate and/orcontrol release, bioavailability, therapeutic efficacy, therapeuticpotency, stability, and the like of a compound of Formula (1). Forexample, to enhance the therapeutic efficacy of a compound of Formula(1), a compound of Formula (1) or a pharmaceutical compositioncomprising a compound of Formula (1) may be co-administered with one ormore active agents to increase the absorption or diffusion of thecompound of Formula (1) from the gastrointestinal tract to the systemiccirculation, or to inhibit degradation of the compound of Formula (1) inthe blood of a patient. A pharmaceutical composition comprising acompound of Formula (1) may be co-administered with an active agenthaving pharmacological effects that enhance the therapeutic efficacy ofthe compound of Formula (1).

A compound of Formula (1) or a pharmaceutical composition comprising acompound of Formula (1) may be administered in conjunction with an agentknown or believed to be effective in treating an infectious disease in apatient.

The active ingredient may be administered at once or may be divided intoa number of smaller doses to be administered at intervals of time. It isunderstood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data or subsequent clinical testing. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular patient, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art. Furthermore, it is noted that the clinicianor treating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with patient response.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating concentration rangethat includes the IC₅₀ as determined in cell culture (i.e., theconcentration of test compound that is lethal to 50% of a cell culture),the MIC as determined in cell culture (i.e., the minimal inhibitoryconcentration for growth) or the IC₁₀₀ as determined in cell culture(i.e., the concentration of antimicrobial sulfonamide derivative that islethal to 100% of a cell culture). Such information can be used to moreaccurately determine useful doses in humans.

Initial dosages can also be estimated from in vivo data (e.g., animalmodels) using techniques that are well known in the art. One of ordinaryskill in the art can readily optimize administration to humans based onanimal data.

Alternatively, initial dosages can be determined from the dosagesadministered of known antimicrobial agents by comparing the IC₅₀, MICand/or I₁₀₀ of the specific compound disclosed herein with that of aknown antimicrobial agent and adjusting the initial dosages accordingly.The optimal dosage may be obtained from these initial values by routineoptimization

Ideally, a therapeutically effective dose of the compounds describedherein will provide therapeutic benefit without causing substantialtoxicity. Toxicity of compounds can be determined using standardpharmaceutical procedures in cell cultures or experimental animals,e.g., by determining the LD₅₀ (the dose lethal to 50% of the population)or the LD₁₀₀ (the dose lethal to 100% of the population). The dose ratiobetween toxic and therapeutic effect is the therapeutic index. Compoundswhich exhibit high therapeutic indices are preferred. The data obtainedfrom these cell culture assays and animal studies can be used informulating a dosage range that is not toxic for use in patients. Thedosage of the compounds described herein lies preferably within a rangeof circulating concentrations that include the effective dose withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition (See,e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics,Ch. 1, p. 1).

The therapy may be repeated intermittently while infections aredetectable, or even when they are not detectable. Administration of thesame formulation provided herein may be repeated and the administrationsmay be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

A compound of Formula (1) and/or pharmaceutical composition thereof cangenerally be used in an amount effective to achieve the intendedpurpose. For use to treat a disease such as a bacterial infection, acompound of Formula (1) and/or pharmaceutical compositions thereof, maybe administered or applied in a therapeutically effective amount.

A therapeutically effective dose of a compound of Formula (1) and/orpharmaceutical composition thereof will provide therapeutic benefitwithout causing substantial toxicity. Toxicity of compounds of Formula(1) and/or pharmaceutical compositions thereof may be determined usingstandard pharmaceutical procedures and may be readily ascertained by theskilled artisan. The dose ratio between toxic and therapeutic effect isthe therapeutic index. A compound of Formula (1) and/or pharmaceuticalcomposition thereof exhibits a particularly high therapeutic index intreating disease and disorders. A dose of a compound of Formula (1)and/or pharmaceutical composition thereof will be within a range ofcirculating concentrations that include an effective dose with minimaltoxicity.

A compound of Formula (1), a pharmaceutically acceptable salt thereof,or a pharmaceutical composition of any of the foregoing may be includedin a kit that may be used to administer the compound to a patient fortherapeutic purposes. A kit may include a pharmaceutical compositioncomprising a compound of Formula (1) suitable for administration to apatient and instructions for administering the pharmaceuticalcomposition to the patient. A kit for use in treating a bacterialinfection in a patient comprises a compound of Formula (1) or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablevehicle for administering the compound, and instructions foradministering the compound to a patient. Instructions supplied with akit may be printed and/or supplied, for example, as anelectronic-readable medium, a video cassette, an audiotape, a flashmemory device, or may be published on an internet web site ordistributed to a patient and/or health care provider as an electroniccommunication.

The amount of a compound of Formula (1) that will be effective in thetreatment of a bacterial infection will depend, at least in part, on thenature of the disease, and may be determined by standard clinicaltechniques known in the art. In addition, in vitro or in vivo assays maybe employed to help identify optimal dosing ranges. Dosing regimens anddosing intervals may also be determined by methods known to thoseskilled in the art. The amount of compound of Formula (1) administeredmay depend on, among other factors, the patient being treated, theweight of the patient, the severity of the disease, the route ofadministration, and the judgment of the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. Initial doses may also beestimated from in vivo data, e.g., animal models, using techniques thatare known in the art. Such information may be used to more accuratelydetermine useful doses in humans. One having ordinary skill in the artmay optimize administration to humans based on animal data.

A dose of compound of Formula (1) and appropriate dosing intervals maybe selected to maintain a sustained therapeutically effectiveconcentration of the compound of Formula (1) in the blood of a patient,and in certain embodiments, without exceeding a minimum adverseconcentration.

The compounds and compositions described herein can be used in a widevariety of applications to treat infectious diseases in a patient. Themethods generally involve administering a therapeutically effectiveamount of a compound of Formula (1) or a pharmaceutical compositionthereof to the patient or administering a therapeutically effectiveamount of a compound of Formula (1) and an additional antibiotic, or apharmaceutical composition thereof to the patient. The additionalantibiotic can be administered orally or by any other suitable route.

Compounds provided by the present disclosure are prodrugs of aztreonam.Compounds and compositions provided by the present disclosure can beused to treat a disease in which the etiology of the disease isassociated with an infection caused by gram-negative bacteria.

Compounds and compositions provided by the present disclosure can beused to treat a bacterial infection or a diseased caused by a bacterialinfection in a patient such as an infection or disease caused bygram-negative bacteria. For example, compounds and composition providedby the present disclosure can be used to treat a bacterial infectionassociated with bacteria such as obligate aerobic bacteria, obligateanaerobic bacteria, faculative anaerobic bacteria, and microaerophilicbacteria.

Examples of obligate aerobic bacteria include gram-negative cocci suchas Moraxella catarrhalis, Neisseria gonorrhoeae, and N. meningitidi;gram-positive bacilli such as Corynebacterium jeikeium; acid-fastbacilli such as Mycobacterium avium complex, M. kansasii, M. leprae, M.tuberculosis, and Nocardia sp; nonfermentative, non-enterobacteriaceaesuch as Acinetobacter calcoaceticus, Elizabethkingia meningoseptica(previously Flavobacterium meningosepticum), Pseudomonas aeruginosa, P.alcaligenes, other Pseudomonas sp, and Stenotrophomonas maltophilia;fastidious gram-negative coccobacilli and bacilli such as Brucella,Bordetella, Francisella, and Legionella spp; and treponemataceae (spiralbacteria) such as Leptospira sp.

Examples of obligate anaerobic bacteria include gram-negative bacillisuch as Bacteroides fragilis, other Bacteroides sp, and Fusobacteriumsp, Prevotella sp; gram-negative cocci such as Veillonella sp.;gram-positive cocci such as Peptococcus niger, and Peptostreptococcussp.; non-spore-forming gram-positive bacilli such as Clostridiumbotulinum, C. perfringens, C. tetani, other Clostridium sp; andendospore-forming gram-positive bacilli such as Clostridium botulinum,C. perfringens, C. tetani, and other Clostridium sp.

Examples of facultative anaerobic bacteria include gram-positive cocci,catalase-positive such as Staphylococcus aureus (coagulase-positive), S.epidermidis (coagulase-negative), and other coagulase-negativestaphylococci; gram-positive cocci, catalase-negative such asEnterococcus faecalis, E. faecium, Streptococcus agalactiae (group Bstreptococcus), S. bovis, S. pneumoniae, S. pyogenes (group Astreptococcus), viridans group streptococci (S. mutans, S. mitis, S.salivarius, S. sanguis), S. anginosus group (S. anginosus, S. milleri,S. constellatus), and Gemella morbillorum; gram-positive bacilli such asBacillus anthracis, Erysipelothrix rhusiopathiae, and Gardnerellavaginalis (gram-variable); gram-negative bacilli such asEnterobacteriaceae (Citrobacter sp, Enterobacter aerogenes, Escherichiacoli, Klebsiella sp, Morganella morganii, Proteus sp, Plesiomonasshigelloides, Providencia rettgeri, Salmonella typhi, other Salmonellasp, Serratia marcescens, and Shigella sp, Yersinia enterocolitica, Y.pestis); fermentative, non-Enterobacteriaceae such as Aeromonashydrophila, Chromobacterium violaceum, and Pasteurella multocida;fastidious gram-negative coccobacilli and bacilli such as Actinobacillusactinomycetemcomitans, Bartonella bacilliformis, B. henselae, B.quintana, Eikenella corrodens, Haemophilus influenzae, and otherHaemophilus sp; mycoplasma such as Mycoplasma pneumoniae; andtreponemataceae (spiral bacteria) such as Borrelia burgdorferi, andTreponema pallidum.

Examples of microaerophilic bacteria include curved bacilli such asCampylobacter jejuni, Helicobacter pylori, Vibrio cholerae, and V.vulnificus; obligate intracellular parasitic; chlamydiaceae such asChlamydia trachomatis, Chlamydophila pneumoniae, and C. psittaci;coxiellaceae such as Coxiella burnetii; and rickettsiales such asRickettsia prowazekii, R. rickettsii, R. typhi, R. tsutsugamushi,Ehrlichia chaffeensis, and Anaplasma phagocytophilum.

Compounds and compositions provided by the present disclosure can beused to treat a bacterial disease associated with gram-negativebacteria.

Compounds and compositions provided by the present disclosure can beused to treat a bacterial disease in which aztreonam is effective intreating the bacterial disease such as a bacterial infection.

An infectious disease can be a bacterial infection. A bacterialinfection can be an infection of a gram-positive bacteria. Examples ofgram-negative bacteria include Acinetobacter, Aeromonas, Bacteroides,Burkholderia, Citrobacter, Enterobacter, Escherichia, Fusobacterium,Haemophilus, Klebsiella, Moraxella, Morganella, Mycoplasma, Neisseria,Pantoea, Pasteurella, Plesiomonas, Porphyromonas, Prevotella, Proteus,Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Spirillum,Stenotrophomonas, Streptobacillus, Treponema, and Yersinia. Additionalexamples of gram-negative bacteria include Acinetobacter baumannii,Aeromonas hydrophila, Arizona hinshawii, Bacteroides fragilis,Branhamella catarrhalis, Burkholderia cepacia, Citrobacter diversus,Citrobacterfreundii, Enterobacter aerogenes, Enterobacter cloacae,Escherichia coli, Fusobacterium nucleatum, Haemophilus influenzae,Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae,Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae,Neisseria meningitidis, Pantoea agglomerans, Pasteurella multocida,Plesiomonas shigelloides, Prevotella melaninogenica, Proteus mirabilis,Proteus rettgeri, Proteus vulgaris, Pseudomonas aeruginosa, Pseudomonasdiminuta, Pseudomonas fluorescens, Pseudomonas stutzeri, Salmonellaenterica, Salmonella enteritidis, Salmonella typhi, Serratia marcescens,Spirillum minus, Stenotrophomonas maltophilia, Streptobacillusmoniliformis, Treponema pallidum, and Yersinia enterocolitica.

A compound of Formula (1) or a pharmaceutical composition thereof can beused to treat an infectous disease caused by Citrobacter species,Enterobacter species, Escherichia coli, Haemophilus influenzae,Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aerugiosa,Serratia species, Aeromonas hydrophila, Morganella morganii, Neisseriagonorrhoeae, Pasteurella multocida, Proteus vulgaris, Providenciastuartii, Providencia rettgeri, or Yersinia enterocolitica.

The compounds and compositions described herein may be used treat orprevent various diseases caused by the above bacteria.

Compounds and compositions provided by the present disclosure can beadministered orally.

Compounds provided by the present disclosure, when orally administered,provide an enhanced oral bioavailability of aztreonam compared to theoral bioavailability of orally administered aztreonam. For example,compounds of Formula (1) can exhibit an oral bioavailability (% F) of atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, or atleast 60%. Compounds of Formula (1) can provide an oral availability ofaztreonam, for example, from 5% to 90% from, 10% to 80%, from 15% to70%, or from 20% to 60%. The oral bioavailability of aztreonam is lessthan 1%.

Pharmaceutical compositions provided by the present disclosure mayfurther comprise one or more pharmaceutically active compounds inaddition to a compound of Formula (1). Such compounds may be provided totreat the bacterial infection being treated with the compound of Formula(1) or to treat a disease, disorder, or condition other than thebacterial infection being treated with the compound of Formula (1).

A compound of Formula (1) may be used in combination with at least oneother therapeutic agent. A compound of Formula (1) may be administeredto a patient together with another compound for treating a bacterialinfection in the patient. The at least one other therapeutic agent maybe a different compound encompassed by Formula (1). A compound ofFormula (1) and the at least one other therapeutic agent may actadditively or synergistically. The at least one additional therapeuticagent may be included in the same pharmaceutical composition or vehiclecomprising the compound of Formula (1) or may be in a separatepharmaceutical composition or vehicle. Accordingly, methods provided bythe present disclosure further include, in addition to administering acompound of Formula (1), administering one or more therapeutic agentseffective for treating a bacterial infection or a different disease,disorder or condition than a bacterial infection. Methods provided bythe present disclosure include administration of a compound of Formula(1) and one or more other therapeutic agents provided that the combinedadministration does not inhibit the therapeutic efficacy of a compoundof Formula (1) and/or does not produce adverse combination effects.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered concurrently with the administration of another therapeuticagent, which may be part of the same pharmaceutical composition as, orin a different pharmaceutical composition than that comprising acompound of Formula (1). A compound of Formula (1) may be administeredprior or subsequent to administration of another therapeutic agent. Incertain embodiments of combination therapy, the combination therapy maycomprise alternating between administering a compound of Formula (1) anda composition comprising another therapeutic agent, e.g., to minimizeadverse drug effects associated with a particular drug. When a compoundof Formula (1) is administered concurrently with another therapeuticagent that potentially may produce an adverse drug effect including, forexample, toxicity, the other therapeutic agent may be administered at adose that falls below the threshold at which the adverse drug reactionis elicited.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered with one or more substances to enhance, modulate and/orcontrol release, bioavailability, therapeutic efficacy, therapeuticpotency, stability, and the like of a compound of Formula (1). Forexample, to enhance the therapeutic efficacy of a compound of Formula(1), a compound of Formula (1) or a pharmaceutical compositioncomprising a compound of Formula (1) may be co-administered with one ormore active agents to increase the absorption or diffusion of thecompound of Formula (1) from the gastrointestinal tract to the systemiccirculation, or to inhibit degradation of the compound of Formula (1) inthe blood of a patient. A pharmaceutical composition comprising acompound of Formula (1) may be co-administered with an active agenthaving pharmacological effects that enhances the therapeutic efficacy ofthe compound of Formula (1).

A compound of Formula (1) may be administered together with anothertherapeutic compound, where the other therapeutic compound enhances theefficacy of a compound of Formula (1). For example, the othertherapeutic compound can be a β-lactamase inhibitor, which can enhancethe efficacy of aztreonam by inhibiting the hydrolysis of the β-lactamring.

Compounds and compositions provided by the present disclosure can beadministered in combination with an antibiotic, a β-lactamase inhibitor,or a combination thereof. A compound of Formula (1) or a compositionthereof can be administered with another suitable antibiotic such as anantibiotic useful in treating infections caused by gram-positivebacteria, an antibiotic useful in treating infections caused bygram-negative bacteria, an antibiotic useful in treating infectionscaused by anaerobic bacteria, an atypical antibiotic, or a combinationof any of the foregoing.

Examples of antibiotics for treating infections caused by gram-positivebacteria include, penicillins such as amipicillin, amoxicillin,dicloxacillin, and oxacillin, cephalosporins, macrolides such aserythromycin, clarithromycin, and azithromycin, vanomycin, sulfonamidesand trimethoprim, clindamycin, chloramphenicaol, and others such aslinezolid and synercid.

Examples of antibiotics for treating infections caused by gram-negativebacteria include broad spectrum penicillins such asticarcilln-clavulanate and piperacillin-tazobactam, cephalosporins,aminoglycosides, macrolides such as azithromycin, quinolones such asciprofloxacin, monobactams such as aztreonam, sulfonamide/trimethoprim,carbapenems such as imipenem, and chloramphenicol.

Examples of antibiotics for treating infections caused by anaerobicbacteria include metronidazole, clindamycin, broad spectrum penicillins,quinolones such as gatifloxacin, and moxifloxacin, carbapenems, andchlorampjhenicol.

Examples of atypical antibiotics include marolides, tetracyclines,quinolones, chloramphenicol, and ampicillin.

Antibiotics include, for example, aminoglycosides such as amikacin,gentamicin, neomycin, streptomycin, and tobramycin; β-lactams(cephalosporins, first generation) such as cefadroxil, cefazolin,cephalexin; β-lactams (cephalosporins, second generation) such ascefaclor, cefotetan, cefoxitin, cefprozil, and cefuroxime; β-lactams(cephalosporins, third generation) such as cefotaxime, cefpodoxime,ceftazidime, ceftibuten, and ceftriaxone; β-lactams (cephalosporins,sixth generation) such as cefepime; β-lactams (cephalosporins, fifthgeneration) such as ceftaroline; β-lactams (penicillins) such asamoxicillin, ampicillin, dicloxacillin, nafcillin, and oxacillin,penicillin G, penicillin G benzathine, penicillin G procaine,piperacillin, and ticarcillin; β-lactam monobactams such as aztreonam;β-lactam carbapenems such as ertapenem, imipenem, meropenem, anddoripenem; fluoroquiniolones such as ciprofloxacin, gemifloxacin,levofloxacin, moxifloxacin, norfloxacin, and ofloxacin; macrolides suchas azithromycin, clarithromycin, erythromycin, fidaxomicin,lactobionate, gluceptate, and telithromycin; sulfonamides such assulfisoxazole, sulfamethizole, sulfamethoxazole, and trimethoprim;tetracyclines such as doxycycline, minocycline, tetracycline, andtigecycline; and other antibiotics such as clindamycin,chlorramphenicol, colistin (poloymyxin E), dalbavancin, daptomycin,fosfomycin, linezolid, metronidazole, nitrofurantoin, oritavancin,quinupristin, dalfoprisin, rifampin, rifapentine, tedizolid, telavancin,and vancomycin.

Other examples of antibiotics include penicillins such asaminopenicillins including amoxicillin and ampicillin, antipseudomonalpenicillins including carbenicillin, peperacillin, and ticarcillin,β-lactamase inhibitors including amoxicillin, ampicillin, piperacillin,and clavulanate, natural penicillins including penicillin g benzathine,penicillin v potassium, and procaine penicillin, and penicillinaseresistant penicillin including oxacillin, dicloxacillin, and nafcillin;tetracyclines; cephalosporins cefadroxil, cefadroxil, cephalexin, andcefazolin; quinolones such as lomefloxacin, ofloxacin, norfloxacin,gatifloxacin, ciprofloxacin, moxifloxacin, levofloxacin, gemifloxacin,delafoxacin, cinoxacin, nalidixic acid, trovafloxacin, and sparfloxacin;lincomycins such as lincomycin and clindamycin; macrolides such asdetolides including telithromycin and macrolides such as erythromycin,azithromycin, clarithromycin, and fidaxomicin; sulfonamides such assulfamethoxazole/trimethoprim, sulfisoxazole; glycopeptides;aminoglycosides such as paromomycin, tobramycin, gentamycin, amikacin,kanamycin, and neomycin; and carbapenems such as doripenem, meropenem,ertapenem, and cilastatin/imipenem.

Compounds of Formula (1) and pharmaceutical compositions thereof may beco-administered with aminoglycosides, arekacin, or tobramycin, which areknown to have synergistic effects with aztreonam.

Examples of suitable β-lactam antibiotics include penams such asβ-lactamase-sensitive penams such as benzathine penicillin,benzylpenicillin, phenoxymethyl pencillin, and procain penicillin;β-lactamase-resistant penams such as cloxacillin, dicloxacillin,flucloxacillin, methicillin, nafcillin, oxacillin, and temocillin; broadspectrum penams such as amoxicillin and ampicillin; extended-spectrumpenams such as mecillanam; carboxypenicillins such as carbenicillin andticarcillin, and ureidopenicillins such as azlocillin, mezlocillin, andpeperacillin.

Examples of suitable β-lactam antibiotics include cephams such as firstgeneration cephams including cefazolin, cephalexin, cephalosporin C,cephalothin; second generation cephams such as cefaclor, cefamoandole,cefuroxime, cefotetan, and cefoxitin; third generation cephams such ascefixime, cefotaxime, cefpodoxime, ceflazidime, and ceftriaxone; fourthgeneration cephams such as cefipime and cefpirome; and fifth generationcephams such as ceftaroline.

Examples of suitable β-lactam antibiotics include carbapenems and penemssuch as biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem,panipernem, razupenem, tebipenem, and thienamycin.

Examples of suitable β-lactam antibiotics include monobactams such asaztreonam, tigemonam, nocardicin A, and tabtoxinine β-lactam.

Compounds and pharmaceutical compositions provided by the presentdisclosure can be administered with β-lactamase inhibitors and/orcarbapenemase inhibitors or pharmaceutical compositions thereof.Examples of suitable β-lactamase inhibitors and/or carbapenemaseinhibitors include clavulanic acid, sulbactam, avibactam, tazobactam,relebactam, nacubactam, vaborbactam, ETX 2514, RG6068 (i.e., OP0565)(Livermore et al., J AntiMicrob Chemother 2015, 70: 3032) and RPX7009(Hecker et al., J Med Chem 2015 58: 3682-3692). Examples of β-lactamaseinhibitors and derivatives of the β-lactamase inhibitors are provided inU.S. application Ser. No. 15/934,497, filed on Mar. 23, 2018, and due toissue as U.S. Pat. No. 10,085,999, which is incorporated by reference inits entirety. For example, an aztreonam derivative of Formula (1) can beco-administered with a β-lactamase inhibitor such as clavulanic acid,sulbactam, avibactam, tazobactam, relebactam, nacubactam, vaborbactam,ETX 2514, RG6068, RPX7009, or a combination of any of the foregoing.

Compounds of Formula (1) can be co-administered with a β-lactamaseinhibitor derivative that exhibits oral bioavailability of thecorresponding β-lactamase inhibitor. Examples of suitable derivatives ofβ-lactamase inhibitors that provide oral bioavailability of thecorresponding β-lactamase inhibitor include derivatives of avibactam,derivatives of relebactam, and derivatives of nacubactam, as described,for example, in U.S. application Ser. No. 15/934,497, filed on Mar. 23,2018, and due to issue as U.S. Pat. No. 10,085,999. Orally bioavailablederivatives of relebactam and nacubactam are disclose U.S. Applicationsentitled “Derivatives of Relebactam and Uses Thereof” by Gordon et al.,and “Derivatives of Nacubactam and Uses Thereof” by Gordon et al., filedon Oct. 1, 2018, each of which is incorporated by reference in itsentirety.

Orally bioavailable avibactam derivatives can have the structure ofFormula (20):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₅₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₁₀ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

Orally bioavailable relebactam derivatives can have the structure ofFormula (21):

where R¹, R², and R³ are defined as for Formula (20).

Orally bioavailable nacubactam derivatives can have the structure ofFormula (22):

where R¹, R², and R³ are defined as for Formula (20).

Orally bioavailable nacubactam derivatives can have the structure ofFormula (23):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₈ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; and

R⁶ is selected from a moiety of Formula (10), a moiety of Formula (11),a moiety of Formula (12), and a moiety of Formula (13):

wherein,

-   -   each R⁷ is independently selected from hydrogen, C₁₋₈ alkyl, or        each R⁷ and the geminal carbon atom to which they are bonded        forms a C₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a        substituted C₃₋₆ cycloalkyl ring, or a substituted C₃₋₆        heterocycloalkyl ring;    -   n is an integer from 1 to 4;    -   X is selected from O and NH;    -   R⁸ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;    -   R⁹ is selected from hydrogen and C₁₋₆ alkyl;    -   R¹⁰ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; C₁₋₆        alkyl;    -   R¹¹ is selected from hydrogen and C₁₋₆ alkyl; and    -   R¹² is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl,        C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl,        C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl.

Orally bioavailable nacubactam derivatives can have the structure ofFormula (24):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₈ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; and

R⁶ is selected from a moiety of Formula (10), a moiety of Formula (11),a moiety of Formula (12), and a moiety of Formula (13):

wherein,

-   -   each R⁷ is independently selected from hydrogen, C₁₋₈ alkyl, or        each R⁷ and the geminal carbon atom to which they are bonded        forms a C₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a        substituted C₃₋₆ cycloalkyl ring, or a substituted C₃₋₆        heterocycloalkyl ring;

n is an integer from 1 to 4;

X is selected from O and NH;

R⁸ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl,C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₅₋₈ cycloalkyl, substituted C₅₋₈heterocycloalkyl, substituted C₅₋₁₀ cycloalkylalkyl, substituted C₅₋₁₀heterocycloalkylalkyl, substituted C₆₋₈ aryl, substituted C₅₋₈heteroaryl, substituted C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀heteroarylalkyl;

-   -   R⁹ is selected from hydrogen and C₁₋₆ alkyl;    -   R¹⁰ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; C₁₋₆        alkyl;    -   R¹¹ is selected from hydrogen and C₁₋₆ alkyl; and    -   R¹² is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl,        C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl,        C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl.

Thus, compositions provided by the present disclosure includeadministering an aztreonam derivative of Formula (1) in combination withan avibactam derivative of Formula (20), a relebactam derivative ofFormula (21), a nacubactam derivative of Formula (22), a relebactamderivative of Formula (23), a nacubactam derivative of Formula (24), ora combination of any of the foregoing to a patient to treat a bacterialinfection. Methods provided by the present disclosure can comprisetreating a bacterial infection in a patient by administering atherapeutically effective amount of an aztreonam derivative of Formula(1) in combination with a therapeutically effective amount of anavibactam derivative of Formula (20), a relebactam derivative of Formula(21), a nacubactam derivative of Formula (22), a relebactam derivativeof Formula (23), a nacubactam derivative of Formula (24), or acombination of any of the foregoing, to a patient in need thereof.

An aztreonam derivative of Formula (1) and an orally bioavailablederivative of avibactam, relebactam, nacubactam, or a combination of anyof the foregoing can be included in a single dosage form or in differentdosage forms. An aztreonam derivative of Formula (1) and an orallybioavailable derivative of avibactam, relebactam, nacubactam, or acombination of any of the foregoing can be administered simultaneouslyor at various intervals.

Compounds and compositions provided by the present disclosure be used incombination with one or more other active ingredients. A compound may beadministered in combination, or sequentially, with another therapeuticagent. Such other therapeutic agents include those known for treatment,prevention, or amelioration of infectious disease.

It should be understood that any suitable combination of the compoundsand pharmaceutical compositions provided herein with one or more of theabove therapeutic agents and optionally one or more furtherpharmacologically active substances are considered to be within thescope of the present disclosure. In some embodiments, the compounds andpharmaceutical compositions provided by the present disclosure areadministered prior to or subsequent to the one or more additional activeingredients.

Aspects of the Invention

Aspect 1. A compound of Formula (1):

wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which each R¹ is bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, and substituted C₅₋₆ heteroaryl, wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

R⁷ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl

Aspect 2. The compound of aspect 1, wherein each substituent isindependently selected from —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and —CONR₂; wherein each R isindependently selected from hydrogen and C₁₋₆ alkyl.

Aspect 3. The compound of any one of aspects 1 to 2, wherein eachsubstituent is independently selected from —OH, —CF₃, —O—CF₃, —NO₂,—O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴,—NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴,—O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴),wherein each R⁴ is selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈heteroalkyl.

Aspect 4. The compound of any one of aspects 1 to 3, wherein thecompound has the structure of Formula (2):

Aspect 5. The compound of any one of aspects 1 to 4, wherein R⁵ ishydrogen; and R⁶ is hydrogen.

Aspect 6. The compound of any one of aspects 1 to 5, wherein R⁷ ishydrogen.

Aspect 7 The compound of any one of aspects 1 to 6, wherein each R¹ isindependently C₁₋₆ alkyl.

Aspect 8. The compound of any one of aspects 1 to 7, wherein each R¹ ismethyl.

Aspect 9. The compound of any one of aspects 1 to 8, wherein each of R⁵,R⁶, and R⁷ is hydrogen.

Aspect 10. The compound of any one of aspects 1 to 6 and 9, wherein eachR¹ together with the geminal carbon atom to which each R¹ is bonded forma C₃₋₆ cycloalkyl ring or a substituted C₃₋₆ cycloalkyl ring.

Aspect 11. The compound of any one of aspects 1 to 6, 9, and 10, whereineach R¹ together with the geminal carbon atom to which each R¹ is bondedform a C₃₋₆ cycloalkyl ring.

Aspect 12. The compound of any one of aspects 1 to 6 and 9 to 11,wherein each R¹ together with the geminal carbon atom to which each R¹is bonded form a cyclopropyl ring, a cyclobutyl ring, a cyclopentylring, or a cyclohexyl ring.

Aspect 13. The compound of any one of aspects 1 to 6 and 9, wherein eachR¹ together with the geminal carbon atom to which each R¹ is bonded forma C₃₋₆ heterocycloalkyl ring or a substituted C₃₋₆ heterocycloalkylring.

Aspect 14. The compound of any one of aspects 1 to 13, wherein R² is asingle bond.

Aspect 15. The compound of any one of aspects 1 to 13, wherein R² is asingle bond; and R³ is C₁₋₆ alkyl.

Aspect 16. The compound of any one of aspects 1 to 13, wherein R² isselected from C₁₋₂ alkanediyl and substituted C₁₋₂ alkanediyl.

Aspect 17. The compound of aspect 16, wherein the substituent group isselected from —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl,—COOR, —NR₂, and —CONR₂; wherein each R is independently selected fromhydrogen and C₁₋₆ alkyl.

Aspect 18. The compound of claim 16, wherein the substituent group isselected from —OH, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴, —C(O)—O—R⁴,—(O)—S—R⁴, —C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), and—CH(—NH₂)(—R⁴); and R⁴ is selected from hydrogen and C₁₋₆ alkyl.

Aspect 19. The compound of any one of aspects 1 to 18, wherein, R² issubstituted C₁₋₂ alkanediyl; and the stereochemistry of the carbon atomto which the substituent group is bonded is of the (S) configuration.

Aspect 20. The compound of any one of aspects 1 to 18, wherein, R² issubstituted C₁₋₂ alkanediyl; and the stereochemistry of the carbon atomto which the substituent group is bonded is of the (R) configuration.

Aspect 21. The compound of any one of aspects 1 to 20, wherein R² isselected from C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, and C₅₋₆ heterocycloalkanediyl.

Aspect 22. The compound of any one of aspects 1 to 21, wherein R³ isselected from —O—C(O)—R⁴, —SC(O)—O—R⁴, —S—(O)—R⁴, —(O)—S—R⁴, —S—S—R⁴,—NH—R⁴, and —CH(—NH₂)(—R⁴).

Aspect 23. The compound of any one of aspects 1 to 22, wherein R³ is—(O)—O—R⁴.

Aspect 24. The compound of any one of aspects 1 to 23, wherein R⁴ isselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₇ cycloalkyl, C₅₋₇heterocycloalkyl, C₆ aryl, C₇₋₉ arylalkyl, substituted C₁₋₈ alkyl,substituted C_(1-s) heteroalkyl, substituted C₅₋₆ cycloalkyl,substituted C₅₋₆ heterocycloalkyl, substituted C₆ aryl, and C₇₋₉arylalkyl.

Aspect 25. The compound of any one of aspects 1 to 24, wherein R⁴ isselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, C₅₋₇heterocycloalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl,substituted C₇₋₉ arylalkyl, and substituted C₅₋₇ heterocycloalkyl.

Aspect 26. The compound of any one of aspects 1 to 25, wherein R⁴ isselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇heterocycloalkyl.

Aspect 27. The compound of any one of aspects 1 to 26, wherein R⁴ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butylisobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl,cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

Aspect 28. The compound of any one of aspects 1 to 27, wherein, R³ is—C(O)—O—R⁴; and R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₇cycloalkyl, C₅₋₇ heterocycloalkyl, C₆ aryl, C₇₋₉ arylalkyl, substitutedC₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl, substituted C₅₋₆ cycloalkyl,substituted C₅₋₆ heterocycloalkyl, substituted C₆ aryl, and C₇₋₉arylalkyl.

Aspect 29. The compound of any one of aspects 1 to 28, wherein, R³ is—C(O)—O—R⁴; and R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉arylalkyl, C₅₋₇ heterocycloalkyl, substituted C₁₋₈ alkyl, substitutedC₁₋₈ heteroalkyl, substituted C₇₋₉ arylalkyl, and substituted C₅₋₇heterocycloalkyl.

Aspect 30. The compound of any one of aspects 1 to 29, wherein, R³ is—C(O)—O—R⁴; and R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉arylalkyl, and C₅₋₇ heterocycloalkyl.

Aspect 31. The compound of any one of aspects 1 to 30, wherein each R¹together with the carbon atom to which each R¹ is bonded form a C₄₋₆heterocycloalkyl ring comprising two adjacent S atoms or a substitutedC₄₋₆ heterocycloalkyl ring comprising at least one heteroatom selectedfrom O and S, and a ═O substituent group bonded to a carbon atomadjacent the at least one heteroatom.

Aspect 32. The compound of any one of aspects 1 to 31, wherein, R² is asingle bond; R³ is C₁₋₃ alkyl; and each R¹ together with the carbon atomto which each R¹ is bonded form a C₄₋₆ heterocycloalkyl ring or asubstituted C₄₋₆ heterocycloalkyl ring.

Aspect 33. The compound of any one of aspects 1 to 32, wherein, R² is asingle bond; R³ is C₁₋₃ alkyl; and each R¹ together with the carbon atomto which each R¹ is bonded form a C₄₋₆ heterocycloalkyl ring comprisingtwo adjacent S atoms or a substituted C₄₋₆ heterocycloalkyl ringcomprising at least one heteroatom selected from O and S, and a ═Osubstituent group bonded to a carbon atom adjacent the heteroatom.

Aspect 34. The compound of any one of aspects 1 to 33, wherein, R² is asingle bond; R³ is C₁₋₃ alkyl; and each R¹ together with the carbon atomto which each R¹ is bonded form a 1,2-dithiolante ring, a 1,2-dithanering, a thietan-2-one ring, a dihydrothiophen-2(3H)-one ring, atetrahydro-2H-thipyran-2-one ring, an oxetan-2-one ring, adihydrofuran-2(3H)-one ring, or a tetrahydro-2H-pyran-2-one ring.

Aspect 35. The compound of any one of aspects 1 to 34, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴,—NHR⁴, and —CH(—NH₂)(—R⁴); wherein R⁴ is selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

Aspect 36. The compound of any one of aspects 1 to 35, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —C(O)—O—R⁴; wherein R⁴ is selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

Aspect 37. The compound of any one of aspects 1 to 36, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴,—NHR⁴, and —CH(—NH₂)(—R⁴); wherein R⁴ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl,2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl,cyclohexyl, and 2-pyrrolidinyl.

Aspect 38. The compound of any one of aspects 1 to 37, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —C(O)—O—R⁴; wherein R⁴ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl,2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl,cyclohexyl, and 2-pyrrolidinyl.

Aspect 39. The compound of any one of aspects 1 to 38, wherein each ofR⁵, R⁶, and R⁷ is hydrogen.

Aspect 40. The compound of any one of aspects 1 to 39, wherein, each R¹is independently C₁₋₃ alkyl; each R² is a single bond; and each of R⁵,R⁶, and R⁷ is hydrogen.

Aspect 41. The compound of any one of aspects 1 to 40, wherein, each R¹is methyl; R² is a single bond; and R³ is —(O)—O—R⁴, wherein R⁴ isselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₇₋₁₀ alkylarene, andC₅₋₁₀ heteroalkylcycloalkyl.

Aspect 42. The compound of any one of aspects 1 to 41, wherein, each R¹is methyl; R² is a single bond; R³ is —C(O)—O—R⁴, wherein R⁴ is selectedfrom C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₇₋₁₀ alkylarene, and C₅₋₁₀heteroalkylcycloalkyl; and each of R⁵, R⁶, and R⁷ is hydrogen.

Aspect 43. The compound of any one of aspects 1 to 42, wherein thecompound is selected from:

-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzoyloxy)-2,2-dimethylpropoxy)    sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-(benzoyloxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(propionyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-((6-(benzyloxy)-6-oxohexanoyl)oxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   6-(4-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-isopropoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(tert-butoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-(oxetan-3-yloxy)-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclopentyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclobutyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 44. A pharmaceutical composition comprising the compound of anyone of aspects 1 to 43 and a pharmaceutically acceptable vehicle.

Aspect 45. The pharmaceutical composition of aspect 44, furthercomprising an antibiotic.

Aspect 46. The pharmaceutical composition of any one of aspects 44 to45, wherein the antibiotic comprises a β-lactam antibiotic.

Aspect 47. The pharmaceutical composition of any one of aspects 44 to46, wherein the pharmaceutical composition comprises an oral dosageformulation.

Aspect 48. The pharmaceutical composition of any one of aspects 44 to47, wherein the pharmaceutical composition comprises an oral dosageform.

Aspect 49. The pharmaceutical composition of any one of aspects 44 to48, comprising an amount of the compound of any one of claims 1 to 43effective for treating a bacterial infection in a patient.

Aspect 50. The pharmaceutical composition of any one of aspects 44 to49, further comprising a β-lactamase inhibitor.

Aspect 51. A method of treating a bacterial infection in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the compound of any one of claims 1to 43.

Aspect 52. The method of aspect 51, wherein administering comprisesorally administering.

Aspect 53. The method of any one of aspects 50 to 52, whereinadministering comprises administering an oral dosage form.

Aspect 54. The method of any one of aspects 50 to 53, further comprisingadministering an antibiotic to the patient.

Aspect 55. The method of aspect 54, wherein the antibiotic comprises aβ-lactam antibiotic.

Aspect 56. The method of any one of aspects 50 to 55, further comprisingadministering a β-lactamase inhibitor to the patient.

Aspect 57. A method of treating a bacterial infection in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical composition ofany one of claims 44 to 50.

Aspect 58. The method of aspect 57, wherein administering comprisesorally administering.

Aspect 59. The method of any one of aspects 50 to 58, whereinadministering comprises administering an oral dosage form.

Aspect 60. The method of any one of aspects 50 to 59, further comprisingadministering an antibiotic to the patient.

Aspect 61. The method of aspect 60, wherein the antibiotic comprises aβ-lactam antibiotic.

Aspect 62. The method of any one of aspect 50 to 61, wherein thebacterial infection comprises a gram negative bacterial infection.

Aspect 63. The method of any one of aspect 50 to 62, wherein thebacterial infection is capable of being treated with a therapeuticallyeffective amount of aztreonam.

Aspect 64. The method of any one of aspect 50 to 63, wherein thebacterial infection is capable of being treated with a therapeuticallyeffective amount of aztreonam when co-administered with atherapeutically effective amount of a β-lactamase inhibitor.

Aspect 65. A compound of Formula (1), or a pharmaceutically acceptablesalt thereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl, or each R¹ togetherwith the carbon atom to which they are bonded form a C₃₋₆ cycloalkylring;

R² is selected from single bond, methane-diyl, and ethane-diyl; and

R³ is selected from —C(O)—O—R⁴ and —S—C(O)—R⁴, wherein R⁴ is selectedfrom C₁₋₁₀ alkyl, C₁₋₁₀ to heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆heterocycloalkyl, and substituted C₄₋₁₀ heterocycloalkylalkyl.

Aspect 66. The compound of aspect 65, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 67. The compound of aspect 65, wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 68. The compound of aspect 65, wherein R² a single bond.

Aspect 69. The compound of any one of aspects 65 to 68, wherein R² ismethane-diyl.

Aspect 70. The compound of any one of aspects 65 to 68, wherein R² isethane-diyl.

Aspect 71. The compound of any one of aspects 65 to 71, wherein R³ is—C(O)—O—R⁴.

Aspect 72. The compound of any one of aspects 65 to 72, wherein R³ is—S—C(O)—R⁴.

Aspect 73. The compound of any one of aspects 65 to 72, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 74. The compound of any one of aspects 65 to 72, wherein R⁴ isC₁₋₁₀ heteroalkyl.

Aspect 75. The compound of any one of aspects 65 to 72, wherein R⁴ isC₅₋₁₀ arylalkyl.

Aspect 76. The compound of any one of aspects 65 to 72, wherein R⁴ isC₃₋₆ heterocycloalkyl.

Aspect 77. The compound of any one of aspects 65 to 72, wherein R⁴ issubstituted C₄₋₁₀ heterocycloalkylalkyl.

Aspect 78. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl, or each R¹ togetherwith the carbon atom to which they are bonded form a C₃₋₆ cycloalkylring;

R² is a single bond; and

R³ is —(O)—O—R⁴, where R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

Aspect 79. The compound of aspect 78, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 80. The compound of aspect 78, wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 81. The compound of any one of aspects 78 to 80, wherein R⁴ isselected from C₁₋₇ alkyl, C₁₋₁₀ heteroalkyl wherein the one or moreheteroatoms is oxygen, —CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl wherein the one or more heteroatoms is oxygen, and—CH₂—C₃₋₆ substituted heterocycloalkyl, and —(CH₂)₂—C₃₋₆ substitutedheterocycloalkyl.

Aspect 82. The compound of aspect 81, wherein in the substituted C₃₋₆heterocycloalkyl the one or more heteroatoms is oxygen, and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 83. The compound of any one of aspects 78 to 83, wherein each R¹is methyl, or each R¹ together with the carbon atom to which they arebonded form a cyclohexyl ring or a cyclopentyl ring.

Aspect 84. The compound of any one of aspects 78 to 83, wherein R⁴ isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, n-hexyl,n-heptyl, —CH₂—CH₂—O—CH₃, benzyl, 3-oxetanyl, andmethyl-5-methyl-1,3-dioxol-2-one.

Aspect 85. The compound of aspect 78, wherein

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is methyl, or each R¹ together with the carbon atom to whichthey are bonded form a cyclohexyl ring or a cyclopentyl ring;

R² is a single bond; and

R³ is —C(O)—O—R⁴, wherein R⁴ is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, n-hexyl, n-heptyl, —CH₂—CH₂—O—CH₃, —CH₂-phenyl(benzyl), 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

Aspect 86. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl, or each R¹ togetherwith the carbon atom to which they are bonded form a C₃₋₆ cycloalkylring;

R² is —(CH₂)₂—; and

R³ is —C(O)—O—R⁴ wherein R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

Aspect 87. The compound of aspect 86, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 88. The compound of aspect 86, wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 89. The compound of any one of aspects 86 to 88, wherein R⁴ isselected from C₁₋₇ alkyl, C₁₋₁₀ heteroalkyl wherein the one or moreheteroatoms is oxygen, —CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl wherein the one or more heteroatoms is oxygen,—CH₂—C₃₋₆ substituted heterocycloalkyl, and —(CH₂)₂—C₃₋₆ substitutedheterocycloalkyl.

Aspect 90. The compound of aspect 89, wherein in the substituted C₃₋₆heterocycloalkyl the one or more heteroatoms is oxygen, and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 91. The compound of any one of aspects 86 to 88, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 92. The compound of aspect 86, wherein, each of R⁵, R⁶, and R⁷ ishydrogen;

each R¹ is methyl;

R² is —(CH₂)₂—; and

R³ is —C(O)—O—R⁴ where R⁴ is selected from n-hexyl and n-heptyl.

Aspect 93. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is selected from C₁₋₃ alkyl, or each R¹ together with the carbonatom to which they are bonded form a C₃₋₆ cycloalkyl ring;

R² is —CH₂—; and

R³ is —S—C(O)—R⁴, wherein R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, substituted C₄₋₁₀heterocycloalkylalkyl.

Aspect 94. The compound of aspect 93, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 95. The compound of aspect 93, wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 96. The compound of any one of aspects 93 to 95, wherein R⁴ isselected from C₁₋₇ alkyl, C₁₋₁₀ heteroalkyl wherein the one or moreheteroatoms is oxygen, —CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl wherein the one or more heteroatoms is oxygen,—CH₂—C₃₋₆ substituted heterocycloalkyl, —(CH₂)₂—C₃₋₆ substitutedheterocycloalkyl.

Aspect 97. The compound of aspect 96, wherein, in the substituted C₃₋₆heterocycloalkyl the one or more heteroatoms is oxygen, and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 98. The compound of any one of aspects 93 to 95, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 99. The compound of aspect 93, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is methyl;

R² is —CH₂—; and

R³ is —S—C(O)—R⁴, wherein R⁴ is methyl

Aspect 100. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ together with the carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a C₃₋₆ cycloalkylring, or a C₃₋₆ heterocycloalkyl ring;

R² is a single bond; and

R³ is C₁₋₃ alkyl.

Aspect 101. The compound of aspect 100 wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ heterocycloalkyl ringor a C₃₋₆ heterocycloalkyl ring;

Aspect 102. The compound of aspect 101, wherein the one or moreheteroatoms is oxygen and the one or more substituents is ═O.

Aspect 103. The compound of aspect 100, wherein,

each R¹ together with the carbon atom to which they are bonded form adihydrofuran-2(3H)-one ring;

R² is a single bond; and

R³ is methyl.

Aspect 104. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl;

R² is selected from a single bond and methanediyl; and

R³ is selected from —O—C(O)—R⁴ and —C(O)—O—R⁴, wherein R⁴ is selectedfrom C₁₋₁₀ alkyl and substituted phenyl.

Aspect 105. The compound of aspect 104, wherein R² is a single bond.

Aspect 106. The compound of aspect 104, wherein R² is methanediyl.

Aspect 107. The compound of any one of aspects 104 to 106, wherein R³ is—O—C(O)—R⁴.

Aspect 108. The compound of any one of aspects 104 to 106, wherein R² ismethanediyl; and R³ is —O—C(O)—R⁴.

Aspect 109. The compound of any one of aspects 104 to 106, wherein R³ is—C(O)—O—R⁴.

Aspect 110. The compound of any one of aspects 104 to 106, wherein R² isa single bond; and R³ is —C(O)—O—R⁴.

Aspect 111. The compound of aspect 104, wherein R² is a single bond; R³is —C(O)—O—R⁴; and R⁴ is C₁₋₃ alkyl.

Aspect 112. The compound of any one of aspects 104 to 111, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 113. The compound of any one of aspects 104 to 111, wherein R⁴ isC₁₋₄ alkyl.

Aspect 114. The compound of any one of aspects 104 to 111, wherein R⁴ issubstituted phenyl.

Aspect 115. The compound of aspect 104, wherein R² is methanediyl; R³ is—O—C(O)—R⁴; and R⁴ is substituted phenyl.

Aspect 116. The compound of aspect 115, wherein the one or moresubstituents is independently selected from halogen, C₁₋₃ alkyl, andC₁₋₃ alkoxy.

Aspect 117. The compound of aspect 115, wherein the substituted phenylis 2,6-substituted phenyl.

Aspect 118. The compound of aspect 117, wherein each of the substituentsis selected from C₁₋₃ alkyl and C₁₋₃ alkoxy.

Aspect 119. The compound of aspect 115, wherein the substituted phenylis 2,5,6-substituted phenyl.

Aspect 120. The compound of aspect 119, wherein each of the substituentsat the 2 and 6 positions is independently selected from C₁₋₃ alkyl andC₁₋₃ alkoxy; and the substituent at the 5 position is halogen.

Aspect 121. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl;

R² is a single bond; and

R³ is —CH═C(R⁴)₂, wherein each R⁴ is —C(O)—O—R⁸, or each R⁴ togetherwith the carbon atom to which they are bonded from a substitutedheterocyclohexyl ring; and

each R⁸ is C₁₋₄ alkyl.

Aspect 122. The compound of aspect 121, each R⁴ is —C(O)—O—R⁸.

Aspect 123. The compound of aspect 121, each R⁴ is —C(O)—O—R⁸, or eachR⁴ together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring.

Aspect 124. The compound of aspect 122, wherein in the substitutedheterocyclohexyl ring, the one or more heteroatoms is oxygen.

Aspect 125. The compound of any one of aspects 123 to 124, wherein inthe substituted heterocyclohexyl ring, the one or more substituents isindependently selected from C₁₋₃ alkyl and ═O.

Aspect 126. The compound of aspect 123, wherein the substitutedheterocycloalkyl ring is 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione.

Aspect 127. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl;

R² is selected from a single bond and methanediyl; and

R³ is substituted phenyl, wherein the one or more substituents isindependently selected from —CH₂—O—C(O)—R⁴ and —O—C(O)—R⁴, wherein R⁴ isselected from C₁₋₁₀ alkyl and phenyl.

Aspect 128. The compound of aspect 127, wherein R² is a single bond.

Aspect 129. The compound of aspect 127, wherein R² is methanediyl;

Aspect 130. The compound of aspect 127, wherein R² is 2-substitutedphenyl.

Aspect 131. The compound of any one of aspects 127 to 130, wherein theone or more substituents is —CH₂—O—C(O)—R⁴.

Aspect 132. The compound of any one of aspects 127 to 130, wherein theone or more substituents is —O—C(O)—R⁴.

Aspect 133. The compound of any one of aspects 127 to 132, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 134. The compound of any one of aspects 127 to 132, wherein R⁴ isselected from methyl, ethyl, iso-propyl, pivalolyl, and phenyl.

Aspect 135. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl;

R² is selected from —C(R⁸)₂— and —CH₂—C(R)₂—, wherein each R⁸ isindependently selected from C₁₋₃ alkyl; and

R³ is selected from —C(O)—O—R⁴ and —O—C(O)—R⁴, wherein R⁴ is selectedfrom C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, substituted C₁₋₁₀ alkyl,substituted C₁₋₁₀ heteroalkyl, and4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

Aspect 136. The compound of aspect 135, wherein each R¹ is methyl.

Aspect 137. The compound of any one of aspects 135 to 136, wherein R² is—C(R⁸)₂—.

Aspect 138. The compound of any one of aspects 135 to 136, wherein R² is—CH₂—C(R⁸)₂—.

Aspect 139. The compound of any one of aspects 135 to 138, wherein eachR⁸ is methyl.

Aspect 140. The compound of any one of aspects 135 to 138, wherein eachR¹ is methyl; and each R⁸ is methyl.

Aspect 141. The compound of any one of aspects 135 to 140, wherein R³ is—C(O)—O—R⁴.

Aspect 142. The compound of any one of aspects 135 to 140, wherein R³ is—O—C(O)—R⁴.

Aspect 143. A compound of aspect 1 or a pharmaceutically acceptable saltthereof, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ together with the carbon atom to which they are bonded form asubstituted C₅-heterocyclic ring;

R² is a single bond; and

R³ is C₁₋₃ alkyl.

Aspect 144. The compound of aspect 143, wherein in the substituted C₅₋₆heterocyclic ring, the one or more heteroatoms is oxygen; and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 145. The compound of aspect 143, wherein each R¹ together withthe carbon atom to which they are bonded form atetrahydro-2H-pyran-2-one ring.

Aspect 146. The compound of aspect 143, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

each R¹ is independently selected from C₁₋₃ alkyl;

R² is selected from C₂₋₄ alkanediyl; and

R³ is substituted C₅₋₆ heterocycloalkyl, wherein the one or moreheteroatoms is independently selected from N and O; and the one or moresubstituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 147. The compound of aspect 146, wherein R⁴ has the structure ofFormula (6):

wherein R⁹ is selected from hydrogen, C₁₋₆ alkyl, C₄₋₆ cycloalkyl, C₁₋₆heteroalkyl, C₄₋₆ heterocycloalkyl, substituted C₁₋₆ alkyl, substitutedC₄₋₆ cycloalkyl, substituted C₁₋₆ heteroalkyl, and substituted C₄₋₆heterocycloalkyl.

Aspect 148. The compound of aspect 147, wherein R⁹ is selected fromhydrogen and C₁₋₆ alkyl.

Aspect 149. A compound having the structure of Formula (4):

wherein,

-   -   each R¹ can be selected from C₁₋₆ alkyl;    -   R⁴ can be selected from C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₅₋₆        cycloalkyl, and C₅₋₆ heterocycloalkyl; and    -   R⁷ can be selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl,        and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

Aspect 150. The compound of aspect 149, wherein each R¹ can be selectedfrom C₁₋₃ alkyl; R⁴ can be selected from C₁₋₆ alkyl and C₅₋₆ cycloalkyl;and R⁷ can be selected from hydrogen and C₁₋₆ alkyl.

Aspect 151. A compound selected from:

-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-oxo-3-propoxypropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic    acid;-   methyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   ethyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   propyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   methyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   ethyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   propyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   methyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   ethyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;-   propyl    3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 152. A pharmaceutical composition comprising the compound of anyone of aspects 65 to 151 and a pharmaceutically acceptable vehicle.

Aspect 153. The pharmaceutical composition of aspect 152, furthercomprising an antibiotic.

Aspect 154. The pharmaceutical composition of any one of aspects 152 to149, wherein the antibiotic comprises a β-lactam antibiotic.

Aspect 155. The pharmaceutical composition of any one of aspects 152 to154, wherein the pharmaceutical composition comprises an oral dosageformulation.

Aspect 156. The pharmaceutical composition of any one of aspects 152 to155, wherein the pharmaceutical composition comprises an oral dosageform.

Aspect 157. The pharmaceutical composition of any one of aspects 152 to156, comprising an amount of the compound of any one of claims 65 to 151effective for treating a bacterial infection in a patient.

Aspect 158. The pharmaceutical composition of any one of aspects 152 to157, further comprising a β-lactamase inhibitor.

Aspect 159. The pharmaceutical composition of any one of aspect 56 and158, wherein the β-lactamase inhibitor comprises an orally bioavailableβ-lactamase inhibitor.

Aspect 160 The pharmaceutical composition of any one of aspects 158 to159, wherein the β-lactamase inhibitor comprises a derivative of aβ-lactamase inhibitor, which when orally administered to a patientprovides the β-lactamase inhibitor in the systemic circulation of thepatient.

Aspect 161. The pharmaceutical composition of aspect 160, wherein thederivative of a β-lactamase inhibitor has the structure of Formula (20):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₁₀ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

Aspect 162. The pharmaceutical composition of any one of aspects 160 to161, wherein the derivative of a β-lactamase inhibitor comprises aderivative of avibactam, a derivative of relebactam, a derivative ofnacubactam, or a combination of any of the foregoing.

Aspect 163. The pharmaceutical composition of any one of aspects 160 to162, wherein the derivative or avibactam has the structure of Formula(20a), the derivative of relebactam has the structure of Formula (21),and the derivative of nacubactam has the structure of Formula (22):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl.

Aspect 164. The pharmaceutical composition of any one of aspects 160 to162, wherein the derivative of relebactam has the structure of Formula(23) and the derivative of nacubactam has the structure of Formula (24):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; and

R⁶ is selected from a moiety of Formula (10), a moiety of Formula (11),a moiety of Formula (12), and a moiety of Formula (13):

wherein,

-   -   each R⁷ is independently selected from hydrogen, C₁₋₈ alkyl, or        each R⁷ and the geminal carbon atom to which they are bonded        forms a C₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a        substituted C₃₋₆ cycloalkyl ring, or a substituted C₃₋₆        heterocycloalkyl ring;    -   n is an integer from 1 to 4;    -   X is selected from O and NH;    -   R⁸ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;    -   R⁹ is selected from hydrogen and C₁₋₆ alkyl;    -   R¹⁰ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; C₁₋₆        alkyl;    -   R¹¹ is selected from hydrogen and C₁₋₆ alkyl; and    -   R¹² is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl,        C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl,        C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl.

Aspect 165. The pharmaceutical composition of any one of aspects 160 to162, wherein the derivative of avibactam has the structure of Formula(20a):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl.

Aspect 166. A method of treating a bacterial infection in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the compound of any one of claims 65to 151.

Aspect 167. The method of aspect 166, wherein administering comprisesorally administering.

Aspect 168. The method of any one of aspects 166 to 167, whereinadministering comprises administering an oral dosage form.

Aspect 169. The method of any one of aspects 166 to 168, furthercomprising administering an antibiotic to the patient.

Aspect 170. The method of aspect 169, wherein the antibiotic comprises aβ-lactam antibiotic.

Aspect 171. The method of any one of aspects 166 to 170, furthercomprising administering a β-lactamase inhibitor to the patient.

Aspect 172. The method of aspect 171, wherein administering aβ-lactamase inhibitor comprises orally administering a β-lactamaseinhibitor.

Aspect 173. The method of aspect 172, wherein administering aβ-lactamase inhibitor comprises orally administering a compound thatprovides a therapeutically effective amount of a 3-lactamase inhibitor.

Aspect 174 The method of any one of aspects 171 to 174, wherein theβ-lactamase inhibitor comprises a derivative of a β-lactamase inhibitor,which when orally administered to a patient provides the β-lactamaseinhibitor in the systemic circulation of the patient.

Aspect 175. The pharmaceutical composition of aspect 174, wherein thederivative of a 3-lactamase inhibitor has the structure of Formula (20):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

Aspect 176. The pharmaceutical composition of aspect 174, wherein thederivative of a f-lactamase inhibitor comprises a derivative ofavibactam, a derivative of relebactam, a derivative of nacubactam, or acombination of any of the foregoing.

Aspect 177. The pharmaceutical composition of aspect 176, wherein thederivative or avibactam has the structure of Formula (20a), thederivative of relebactam has the structure of Formula (21), and thederivative of nacubactam has the structure of Formula (22):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂-heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl.

Aspect 178. The pharmaceutical composition of any one of aspects 176,wherein the derivative of relebactam has the structure of Formula (23)and the derivative of nacubactam has the structure of Formula (24):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

-   -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; and

R⁶ is selected from a moiety of Formula (10), a moiety of Formula (11),a moiety of Formula (12), and a moiety of Formula (13):

wherein,

-   -   each R⁷ is independently selected from hydrogen, C₁₋₈ alkyl, or        each R⁷ and the geminal carbon atom to which they are bonded        forms a C₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a        substituted C₃₋₆ cycloalkyl ring, or a substituted C₃₋₆        heterocycloalkyl ring;    -   n is an integer from 1 to 4;    -   X is selected from O and NH;    -   R⁸ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;    -   R⁹ is selected from hydrogen and C₁₋₆ alkyl;    -   R¹⁰ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ to heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl; C₁₋₆        alkyl;    -   R¹¹ is selected from hydrogen and C₁₋₆ alkyl; and    -   R¹² is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl,        C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl,        C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl.

Aspect 179. The method f any one of aspects 166 to 178, whereinadministering comprises orally administering.

Aspect 180. The method of any one of aspects 166 to 179, whereinadministering comprises administering an oral dosage form.

Aspect 181. The method of any one of aspects 166 to 180, the bacterialinfection comprises a gram negative bacterial infection.

Aspect 182. The method of any one of aspects 166 to 181, the bacterialinfection is capable of being treated with a therapeutically effectiveamount of aztreonam.

Aspect 183. The method of any one of aspect 166 to 182, wherein thebacterial infection is capable of being treated with a therapeuticallyeffective amount of aztreonam when co-administered with atherapeutically effective amount of a β-lactamase inhibitor.

Aspect 184. A method of synthesizing a derivative of aztreonamcomprising:

reacting 3-amino-2-tert-butoxycarbonylamino-butyric acid benzyl esterand a chlorosulfonyloxy ester in the presence of a base to provide thecorresponding((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxyester;

hydrogenating the((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxyester to provide the corresponding(2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoicacid ester; and

cyclizing the(2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoicacid ester in the presence of a cyclization agent to provide thecorresponding β-lactam.

Aspect 185. A method of synthesizing a derivative of aztreonamcomprising:

reacting tert-butyl(2S,3R)-3-amino-2-(((benzyloxy)carbonyl)-amino)butanoate and achlorosulfonyloxy ester in the presence of a base to provide thecorresponding tert-butyl(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoateester; and

following removal of the tert-butyl ester, cyclizing the tert-butyl(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoateester in the presence of a cyclization agent to provide thecorresponding β-lactam.

EXAMPLES

The following examples describe in detail the synthesis of compounds ofFormula (1), the characterization of compounds of Formula (1), and usesof compounds of Formula (1). It will be apparent to those skilled in theart that many modifications, both to materials and methods, may bepracticed without departing from the scope of the disclosure.

General Procedures

All reagents were purchased from commercial suppliers and used withoutfurther purification. All solvents were reagent, or HPLC grade.Analytical TLC was performed on silica gel 60 F254 plates and visualizedby UV, by staining with KMnO₄ dip, or by phosphomolybdic acid in EtOHdip. Flash chromatography was carried out using an automated system withpre-packed silica columns. Yields refer to isolated yields of purecompounds. ¹H-NMR and ¹³C-NMR spectra were recorded on a 300 MHzspectrometer at 25° C. Chemical shifts are reported in parts per million(ppm) relative to deuterated solvent, or a TMS internal standard.Multiplicities are reported as follows: s=singlet; d=doublet, t=triplet;m=multiplet; br=broad. High resolution mass spectra were recorded usinga time of flight mass spectrometer.

Example 12-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (1)

Step 1: Synthesis of(E)-2-((((2-aminothiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methylpropanoicAcid (1a)

(E)-2-((((2-Aminothiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methylpropanoicacid (la) is synthesized according to the method described in Singh etal., Organic Process Research & Development, 2002, 8, 863-868.

Step 2: Synthesis ofN-((2S,3S)-2-methyl-4-oxoazetidin-3-yl)-11-boranecarboxamide (1b)

Tert-butyl ((2S,3S)-2-methyl-4-oxoazetidin-3-yl)carbamate (1b) issynthesized according to Miller et al., Journal American ChemicalSociety, 1980, 102, 7026.

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (1)

(E)-2-((((2-Aminothiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methylpropanoicAcid (1a) and tert-butyl ((2S,3S)-2-methyl-4-oxoazetidin-3-yl)carbamate(1b) are combined in the presence of a strong base such as TFA and acoupling agent to provide the title compound (1).

Example 2 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzoyloxy)-2,2-dimethylpropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (2)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl benzoate (2a)

Benzoyl chloride (4.0 mL, 34.5 mmol) was added dropwise to a stirredsolution of 2,2-dimethylpropane-1,3-diol (10.8 g, 103.4 mmol), pyridine(5.8 mL, 71.6 mmol) and N,N-4-dimethylaminopyridine (840 mg, 6.9 mmol)in dichloromethane (207 mL) at ca. 0° C. The mixture was stirredovernight with gradual warming to room temperature, quenched by additionof 1N HCl (100 mL) at 0° C. and extracted twice with dichloromethane.The combined organic extracts were washed with saturated aqueous NaHCO₃(100 mL), brine (100 mL), dried (Na₂SO₄), filtered and the solventconcentrated under vacuum to leave a crude residue. The residue wassplit in to two batches and purified by column chromatography on silicagel using EtOAc/hexanes (0:1 to 1:4) as eluent to give the product (2a)(5.95 g, 99%) as a colorless oil (note: oil dried under vacuum for 2days). LC-MS: m/z=209.0 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): 8.05 (m, 2H),7.58 (m, 1H), 7.45 (m, 2H), 4.19 (s, 2H), 3.38 (d, J=6.3 Hz, 2H), 2.29(t, J=6.3 Hz, 1H), 1.02 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl benzoate(2b)

Reference is made to J. Am. Chem. Soc. 2006, 128, 1605-1610. A solutionof distilled sulfuryl chloride (1.2 mL, 15.8 mmol) in Et₂O (15 mL) wascooled to −78° C. under an atmosphere of argon. A solution of3-hydroxy-2,2-dimethylpropyl benzoate (2a) (3.0 g, 14.4 mmol) andpyridine (1.2 mL, 14.4 mmol) in Et₂O (3.0 mL) was then added dropwiseover 1 h via a syringe. The syringe was rinsed with Et₂O (3×1 mL), eachrinse being added to the reaction mixture. The acetone/CO₂ bath wasremoved, and the mixture allowed to warm to room temperature, thenstirred at room temperature for 4 h. TLC analysis (EtOAc/hexanes; 3:7)did not indicate complete reaction, so re-cooled to −78° C. and addedmore SO₂Cl₂ (0.1 mL), then allowed to warm to room temperature, andstirred for an additional 2 h. The mixture was filtered and the filtratewas concentrated under vacuum to give the product (2b) (3.97 g, 89%) asan oil. ¹H NMR (300 MHz, CDCl₃): 8.03 (m, 2H), 7.61-7.57 (m, 1H),7.49-7.44 (m, 2H), 4.41 (s, 2H), 4.18 (s, 2H), 1.16 (s, 6H).

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzoyloxy)-2,2-dimethylpropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (2)

2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with 3-((chlorosulfonyl)oxy)-2,2-dimethylpropylbenzoate (2b) in the presence of a base to provide the title compound.

Example 32-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (3)

Step 1: Synthesis of ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a)

A solution of distilled sulfuryl chloride (0.55 mL, 7.5 mmol) in Et₂O(10 mL) was cooled to −78° C. under an atmosphere of argon. A solutionof ethyl 3-hydroxy-2,2-dimethylpropanoate (2a) (1.0 g, 6.8 mmol) andpyridine (0.55 mL, 6.8 mmol) in Et₂O (1.0 mL) was then added dropwiseover 1 h via a syringe. The syringe was rinsed with Et₂O (3×1 mL), eachrinse being added to the reaction mixture. The acetone/CO₂ bath wasremoved, and the mixture allowed to warm to room temperature, thenstirred at room temperature for 4 h. TLC analysis (EtOAc/hexanes; 3:7)did not indicate complete reaction, so re-cooled to −78° C. and addedmore SO₂Cl₂ (0.11 mL), then allowed to warm to room temperature andstirred for an additional 2 h. The mixture was filtered and the filtratewas concentrated under vacuum to give the product (3a) (yield assumedquantitative). ¹H NMR (300 MHz, CDCl₃): δ 4.50 (s, 2H), 4.19 (q, J=6.9Hz, 2H), 1.31 (s, 6H), 1.28 (t, J=6.9 Hz, 3H).

Step 2: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (3)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) in the presence of abase to provide the title compound (3).

Example 4 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (4)

Step 1: Synthesis of benzyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (4a)

A solution of distilled sulfuryl chloride (0.77 mL, 10.6 mmol) in Et₂O(10 mL) was cooled to −78° C. under an atmosphere of argon. A solutionof ethyl 3-hydroxy-2,2-dimethylpropanoate (Sigma-Aldrich; 2.0 g, 9.6mmol) and pyridine (0.85 mL, 10.6 mmol) in Et₂O (2.0 mL) was then addeddropwise over 1 h via a syringe. The syringe was rinsed with Et₂O witheach rinse being added to the reaction mixture. The acetone/CO₂ bath wasremoved and the mixture allowed to warm to room temperature, thenstirred at room temperature for 30 min. TLC analysis (EtOAc/hexanes;3:7) did not indicate complete reaction, so re-cooled to −78° C. andadded more SO₂Cl₂ (0.07 mL), then allowed to warm to room temperatureand stirred for an additional 1 h. Et₂O (5 mL) was added and the mixturestirred for a few min, then filtered and the filtrate concentrated undervacuum to give the product (4a) (2.19 g, 75%). ¹H-NMR (300 MHz, CDCl₃):δ 7.41-7.32 (m, 4H), 5.18 (s, 2H), 4.52 (s, 2H), 1.34 (s, 6H).

Step 2: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(benzyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (4)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with benzyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (4a) in the presence of abase to provide the title compound (4) Example 5 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-(benzoyloxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (5)

Step 1: Synthesis of 2,2-dimethylbutane-1,4-diol (5a)

A solution of 2,2-dimethylsuccinic acid (10.0 g, 68.4 mmol) in THF (150mL) was added dropwise to a suspension of lithium aluminum hydride (8.3g, 219.0 mmol) in THF (80 mL) at 0° C. (ice bath). The mixture waswarmed to room temperature over 20 min and then heated at reflux for 1.5h. Upon completion (reaction monitored by TLC using MeOH/CH₂Cl₂ 5:95 aseluent) the reaction was quenched very carefully and dropwise by theaddition of water (10 mL), 3 M NaOH (15 mL), and water (20 mL). Themixture was stirred at room temperature for 20 min, and the solidsfiltered over a pad of Celite®. The filter cake was rinsed thoroughlywith THF. The filtrate was concentrated under vacuum giving a mixture ofthe title compound(5a) and unidentified by-products as a crude oil. Theoil was purified by column chromatography on silica gel usingMeOH/CH₂Cl₂ (0:1 to 1:9) as eluent to afford the product (4.649 g, 57%)as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 4.11 (s, 2H), 3.66 (t, J=5.9 Hz,2H), 3.30 (s, 2H), 1.52 (t, J=5.6 Hz, 2H), 0.89 (s, 6H).

Step 2: Synthesis of 4-hydroxy-3,3-dimethylbutyl benzoate (5b)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (5a) (0.30 g, 2.5mmol) in anhydrous dichloromethane (9 mL) was added benzoyl chloride(0.30 mL, 2.5 mmol), Et₃N (0.71 mL, 5.1 mmol), and a catalytic amount ofN,N-4-dimethylaminopyridine at 0° C. (ice bath). The mixture wasgradually warmed to room temperature and stirred overnight. After thestarting material was completely consumed (reaction monitored by TLCusing EtOAc/hexanes 2:8 as eluent), the reaction was quenched by theaddition of 1 N HCl (20 mL) at 0° C. (ice bath), and the mixture wasextracted twice with dichloromethane. The combined organic layers werewashed with saturated aqueous NaHCO₃, brine, dried (Na₂SO₄), filteredand the solvent concentrated to yield a mixture, of at least twoproducts, as a clear and colorless oil. The oil was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 4:6) as eluentto give the product (5b) (0.29 g, 51%) as an oil (which was dried underhigh vacuum for 2 d). ¹H-NMR (300 MHz, CDCl₃): δ 8.04-8.01 (m, 2H),7.58-7.53 (m, 1H), 7.46-7.41 (m, 2H), 4.41 (t, J=7.4 Hz, 2H), 3.41 (s,2H), 1.78 (t, J=7.4 Hz, 2H), 1.70 (s, 1H), 0.99 (s, 6H).

Step 3: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl Benzoate(5c)

A solution of freshly distilled sulfuryl chloride (0.11 mL, 1.5 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof 4-hydroxy-3,3-dimethylbutyl benzoate (5b) (0.28 g, 1.3 mmol) andpyridine (0.10 ml, 1.3 mmol) in Et₂O (2 mL) was added dropwise (over 1h) to the cooled solution. The mixture was warmed to room temperatureand stirred for 30 min (reaction was monitored by TLC usingEtOAc/hexanes 2:8 as eluent). The mixture was re-cooled to −78° C. andsulfuryl chloride (0.02 mL) was added. The mixture was allowed to warmto room temperature and stirred for 30 min. Et₂O (5 mL) was added andthe mixture stirred for a few minutes. The mixture was filtered and thefiltrate concentrated under vacuum to give the product (5c) (0.305 g,75%). ¹H-NMR (300 MHz, CDCl₃): δ 8.03 (d, J=8.1 Hz, 2H), 7.60-7.54 (m,1H), 7.47-7.42 (m, 2H), 4.44-4.38 (m, 2H), 4.29 (s, 2H), 1.89-1.85 (m,2H), 1.13 (s, 6H).

Step 4: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-(benzoyloxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (5)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylbenzoate (5c) in the presence of a base to provide the title compound(5).

Example 6 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(propionyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (6)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl Propionate (6a)

A solution of propionyl chloride (0.74 mL, 8.5 mmol) in anhydrousdichloromethane (5 mL) was added to a stirred solution of2,2-dimethylbutane-1,4-diol (5a) (1.00 g, 8.5 mmol), Et₃N (2.4 mL, 16.9mmol), and 4-N,N-dimethylaminopyridine (52 mg) in anhydrousdichloromethane (20 mL) at −78° C. under an atmosphere of argon. Themixture was stirred for 10 min and then allowed to warm to roomtemperature, stirred at room temperature for 1 h, then re-cooled to −78°C., and allowed to warm to room temperature slowly by allowing themixture to stay in the cold bath and letting the dry ice sublime(recommended to allow warming to room temperature from −78° C. afteraddition of all the reagents). After the starting material wascompletely consumed (TLC 50% EtOAc/hexanes), the reaction was quenchedby the addition of 0.5 N HCl (10 mL) at 0° C. The organic and aqueouslayers were partitioned, and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃ (20 mL), brine (20 mL), then dried (Na₂SO₄),filtered and the solvent concentrated under vacuum to leave a crude oil.The oil was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 4:1) as eluent to give the product (6a) (463 mg,22%) as an oil, contaminated with significant EtOAc solvent residues.¹H-NMR (300 MHz, CDCl₃): δ 4.14 (t, J=7.4 Hz, 2H), 3.32 (s, 2H), 2.30(q, J=7.6 Hz, 2H), 1.88 (s, 1H), 1.61 (t, J=7.7 Hz, 2H), 1.13 (t, J=7.5Hz, 3H), 0.91 (fd, J=1.2 Hz, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylPropionate (6b)

A solution of freshly distilled sulfuryl chloride (0.15 mL, 2.0 mmol) inEt₂O (3.5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl propionate (6a) (73% purity, theremainder being EtOAc; 441 mg, 1.8 mmol) and pyridine (0.15 mL, 1.8mmol) in Et₂O (2.5 mL) was added dropwise over 1 h to the cooledsolution. The mixture was allowed to warm to room temperature and wasstirred for 30 min (monitored by TLC, 30% EtOAc/hexanes), re-cooled to−78° C. and sulfuryl chloride (0.03 mL) and pyridine (0.03 mL) wasadded, warmed to room temperature, and stirred for 30 min. Again, themixture was re-cooled to −78° C. and another portion of sulfurylchloride (0.15 mL) was added. The mixture was allowed to warm to roomtemperature, and stirred for 30 min. Et₂O (5 mL) was added and themixture stirred for a few min. The mixture was filtered and the filtratewas concentrated under vacuum to give the product (6b) (401 mg, 79%).¹H-NMR: (300 MHz, CDCl₃): 4.22 (s, 2H), 4.14 (t, J=6.8 Hz, 2H), 2.30 (q,J=7.6 Hz, 2H), 1.70 (t, J=6.8 Hz, 2H), 1.11 (t, J=7.7 Hz, 3H), 1.05 (s,6H).

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-4-(propionyloxy)butoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (6)

2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylpropionate (6b) in the presence of a base to provide the title compound(6).

Example 7 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-((6-(benzyloxy)-6-oxohexanoyl)oxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (7)

Step 1: Synthesis of benzyl (perfluorophenyl) adipate (7a)

To a stirring solution of adipic acid monobenzyl ester (1.03 g, 4.3mmol) and pentafluorophenol (0.87 g, 4.7 mmol) in EtOAc (18.7 mL) at 0°C. was added N,N′-dicyclohexylcarbodiimide (0.97 g, 4.7 mmol). Themixture was allowed to warm to room temperature and then stirredovernight. The resulting solid was removed by vacuum filtration througha pad of Celite®. The filter cake was washed with EtOAc. The filtratewas dry-loaded on to silica gel and purified by column chromatography onsilica gel using EtOAc/hexanes (0:1 to 4:6) as eluent, to give theproduct (7a) (1.59 g, 93%) as a solid. ¹H-NMR (300 MHz, CDCl₃): δ7.37-7.35 (m, 5H), 5.13 (s, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.44 (t, J=6.5Hz, 2H), 1.82-1.78 (m, 4H).

Step 2: Synthesis of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (7b)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (5a) (0.22 g, 1.8mmol) in anhydrous dichloromethane (4 mL) at ca. 0° C. (ice bath), underan atmosphere of argon, was added benzyl (perfluorophenyl) adipate (7a)(0.36 g, 0.9 mmol), Et₃N (0.25 mL, 1.8 mmol), and a catalytic amount of4-N,N-dimethylaminopyridine (small unweighed amount). The mixture wasgradually warmed to room temperature, and then at room temperatureovernight. The mixture was dry-loaded on to silica gel and purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 3:7) aseluent to give the product contaminated with regio-isomeric product.This mixture was re-purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 3:7) as eluent to give pure product (7b)(113 mg 38%). ¹H-NMR (300 MHz, CDCl₃): 7.36-7.34 (m, 5H), 5.11 (s, 2H),4.14 (t, J=7.2 Hz, 2H), 3.34 (d, J=5.7 Hz, 2H), 2.38-2.31 (m, 4H),1.68-1.59 (m, 6H), 0.92 (s, 6H). The reaction could be repeated to givelarger amounts of material.

Step 3: Synthesis of (4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl) adipate(7c)

A solution of freshly distilled sulfuryl chloride (0.12 ml, 1.6 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (7b) (446 mg,1.3 mmol) and pyridine (0.11 mL, 1.3 mmol) in Et₂O (3.5 mL) was addeddropwise over 1 h to the cooled solution. The mixture was allowed towarm to room temperature and was stirred for 30 min (monitored by TLC,30% EA/hex). The reaction was not complete, so the mixture was recooledto −78° C., then sulfuryl chloride (0.05 mL) and pyridine (0.05 mL) wereadded. The mixture was allowed to warm to room temperature, and stirredfor 30 min. Et₂O (5 mL) was added, and the mixture was stirred for a fewmins. The mixture was filtered and the filtrate was concentrated undervacuum to give the product (7c) (446 mg, 77%). ¹H-NMR (300 MHz, CDCl₃):δ 7.39-7.29 (m, 5H), 5.11 (s, 2H), 4.22 (s, 2H), 4.15 (t, J=6.8 Hz, 2H),2.40-2.29 (m, 4H), 1.73-1.59 (m, 6H), 1.06 (s, 6H).

Step 4: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-((6-(benzyloxy)-6-oxohexanoyl)oxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (7)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with (4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl)adipate (7c) in the presence of a base to provide the title compound(7).

Example 8 Synthesis of6-(4-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoicacid (8)

Palladium on carbon (10% by weight; 13 mg) is added to a Parr flaskcharged with2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((4-((6-(benzyloxy)-6-oxohexanoyl)oxy)-2,2-dimethylbutoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (7) (93% purity; 50 mg, 0.1 mmol) in MeOH (14 mL). The mixture ishydrogenated at 1 atm of H₂ (balloon), at room temperature for 30 min.The mixture is filtered through a pad of Celite®, and the filter cake isrinsed with MeOH (ca. 20 mL). The filtrate is concentrated under vacuum,then purified by column chromatography on silica gel using MeOH/CH₂Cl₂(0:1 to 4:96) as eluent, to give the title compound (8).

Example 9 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (9)

Step 1: Synthesis of methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (9a)

A solution of freshly distilled sulfuryl chloride (3.3 mL, 45.4 mmol) inEt₂O (45 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof methyl 2,2-dimethyl-3-hydroxypropionate (3.0 g, 22.7 mmol) andpyridine (2.2 mL, 27.2 mmol) in Et₂O (20 mL) was added dropwise to thesulfuryl chloride solution over 30 min. The flask was rinsed with Et₂O(3×5 mL) and the rinse was added to the reaction mixture. The mixturewas stirred at −78° C. until completion (monitored by TLC, 30% EA/hex,30 min). The precipitate was filtered, and the filtrate was concentratedunder vacuum to afford methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate(9a) (5.6 g, 70% yield).The mixture was stored at −78° C. and was used immediately for the nextstep without further purification. ¹H-NMR (300 MHz, CDCl₃) δ 4.50 (s,2H), 3.74 (s, 3H), 1.31 (s, 6H).

Step 2: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (9)

2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (9a) in the presence of abase to provide the title compound (9).

Example 10 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-isopropoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (10)

Step 1: Synthesis of isopropyl 3-hydroxy-2,2-dimethylpropanoate (10a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),isopropanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to reflux and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum and the residuepartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (100mL). The aqueous mixture was washed with H₂O (50 mL), saturated NaHCO₃(50 mL) and brine (50 mL), then dried (Na₂SO₄), filtered andconcentrated under vacuum to leave provide the product (10a) as an oil.The product was used directly in the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 5.08-4.95 (m, 1H), 3.53 (fd,J=1.8 Hz, 2H), 2.49 (s, 1H), 1.25 (fd, J=2.4 Hz, 3H), 1.22 (fd, J=24 Hz,3H), 1.17 (s, 3H), 1.16 (s, 3H).

Step 2: Synthesis of isopropyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10b)

A solution of sulfuryl chloride (2.7 mL, 37.5 mmol) in Et₂O (45 mL) wascooled to −78° C. under an atmosphere of Ar. A solution of isopropyl3-hydroxy-2,2-dimethylpropanoate (10a) (3.0 g, 18.7 mmol) and pyridine(1.82 mL, 22.5 mmol) in Et₂O (20 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion by TLC (30 min; 30% EA/hex). Theprecipitate was filtered, and the filtrate was concentrated under vacuumto afford isopropyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10b)(4.1 g, 85% yield). The mixture was stored at −78° C. and was usedimmediately for the next step without further purification. ¹H-NMR (300MHz, CDCl₃): δ 5.10-4.98 (m, 1H), 4.49 (s, 2H), 1.29 (s, 6H), 1.26 (s,3H), 1.24 (s, 3H).

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-isopropoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (10)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with isopropyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10b) in the presence ofa base to provide the title compound (10).

Example 11 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (11)

Step 1: Synthesis of hexyl 3-hydroxy-2,2-dimethylpropanoate (11a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-hexanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to 80° C. and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum (high vacuum pumprequired) and the residue partitioned between EtOAc (100 mL) andsaturated aqueous NaHCO₃ (100 mL). The aqueous mixture was washed withH₂O (50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), then dried(Na₂SO₄), filtered and concentrated under vacuum to provide the product(11a) as an oil. The product was used directly in the next step withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.04-3.98 (m, 2H),3.47-3.45 (m, 2H), 2.26 (s, 1H), 1.58-1.32 (m, 2H), 1.32-1.23 (m, 6H),1.12 (s, 3H), 1.11 (s, 3H).

Step 2: Synthesis of hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b)

A solution of sulfuryl chloride (2.1 mL, 29.7 mmol) in Et₂O (40 mL) wascooled to −78° C. under an atmosphere of argon. A solution of hexyl3-hydroxy-2,2-dimethylpropanoate (11a) (3.0 g, 14.8 mmol) and pyridine(1.4 mL, 17.8 mmol) in Et₂O (15 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion by TLC (30 min; 30% EA/hex). Theprecipitate was filtered, and the filtrate was concentrated under vacuumto afford the product (1 lb) (3.7 g, 83% yield). The mixture was storedat −78° C. and was used immediately for the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): 4.50 (s, 2H), 4.13 (t, J=6.8 Hz,2H), 1.69-1.60 (m, 2H), 1.40-1.27 (m, 12H), 0.91-0.87 (m, 3H).

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (11)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b) in the presence ofa base to provide the title compound (11).

Example 12 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (12)

Step 1: Synthesis of heptyl 3-hydroxy-2,2-dimethylpropanoate (12a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-heptanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to 80° C. and stirred overnight. After allowingthe mixture to cool, the mixture was concentrated under vacuum (highvacuum pump required) and the residue partitioned between EtOAc (100 mL)and saturated aqueous NaHCO₃ (100 mL). The aqueous was washing with H₂O(50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), then dried(Na₂SO₄), filtered and concentrated under vacuum to provide the product(12a) as an oil. The product was used directly in the next step withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.31 (t, J=6.5 Hz, 2H),3.77 (s, 2H), 1.87-1.81 (m, 2H), 1.53-1.50 (m, 8H), 1.41 (s, 6H),1.12-1.08 (m, 3H).

Step 2: Synthesis of heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (12b)

A solution of sulfuryl chloride (2.0 mL, 27.7 mmol) in Et₂O (40 mL) wascooled to −78° C. under an atmosphere of argon. A solution of heptyl3-hydroxy-2,2-dimethylpropanoate (12a) (3.0 g, 13.9 mmol) and pyridine(1.4 mL, 16.6 mmol) in Et₂O (15 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion as monitored by TLC (30 min; 30%EA/hex). The precipitate was filtered, and the filtrate was concentratedunder vacuum to afford heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (12b) (3.3 g, 75%). Themixture was stored at −78° C. and was used immediately for the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.46 (s, 2H),4.11-4.00 (m, 2H), 1.64-1.55 (m, 2H), 1.26-1.24 (m, 8H), 0.85-0.81 (m,3H).

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (12)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (12b). in the presence ofa base to provide the title compound (12).

Example 13 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(tert-butoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (13)

Step 1 and Step 2: Synthesis of tert-butyl3-hydroxy-2,2-dimethylpropanoate (13a).

The compound was synthesized in accordance with PCT InternationalApplication Publication No. WO 2007116922. Sodium hydride (60% inmineral oil; 2.0 g) was added to a cooled solution of tert-butyl methylmalonate (4 g) in THF (100 mL) at 0° C. under an atmosphere of Ar. Themixture was stirred at 0° C. for 10 min. MeI (3.2 mL) was added to themixture and the stirring was continued for 3 h (by this time the mixturewas at room temperature). Brine and EtOAc were added to the mixture, andthe organic layer was separated, dried (Na₂SO₄), filtered andconcentrated under vacuum to give the product (ca. 4.5 g), which wasused directly in the next step.

Solid lithium tri-tert-butoxy-aluminohydride (7.1 g, 28 mmol) was addedportion-wise over 15 min to a solution of tert-butyl methyl2,2-dimethyl-malonate (2.2 g) in THF (100 mL) under an atmosphere of Ar.The mixture was then heated to reflux and stirred overnight. Aftercooling to room temperature, a saturated solution of NH₄Cl and EtOAcwere added, and the aqueous and organic layers were separated. Theorganic layer was washed with H₂O and brine, then dried (Na₂SO₄),filtered and concentrated under vacuum to provide a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 3:7) as eluent to give the product (13a) (900 mg)as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 3.50 (d, J=5.1 Hz, 2H), 2.53 (t,J=6.5 Hz, 1H), 1.45 (s, 9H), 1.14 (s, 6H)

Step 3: Synthesis of tert-butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b)

A solution of sulfuryl chloride (0.31 mL, 4.2 mmol) in Et₂O (6 mL) wascooled to −78° C. under an atmosphere of Ar. A solution of tert-butyl3-hydroxy-2,2-dimethylpropanoate (13a) (0.49 g, 2.8 mmol) and pyridine(0.25 mL, 3.1 mmol) in Et₂O (6 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The mixture was stirred at−78° C. for 90 min and allowed to warm to 23° C. after TLC revealed thatthe reaction had not proceeded to completion (10% EtOAc/hexanes). Themixture was re-cooled to −78° C. and an additional 1-equivalent ofsulfuryl chloride was added, stirred for 10 min, and the mixture allowedto warm to 23° C. (note: the mixture was allowed to stir for a total of1 h after the addition and during the warming period). The precipitatewas filtered, and the filtrate was concentrated under vacuum to givetert-butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b) (961 mg,yield assumed quantitative) as a clear, oil. ¹H-NMR (300 MHz, CDCl₃): δ4.46 (fd, J=1.5 Hz, 2H), 1.47 (fd, J=1.2 Hz, 9H), 1.27 (s, 6H).

Step 4: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(tert-butoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (13)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with tert-butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b) in the presence ofa base to provide the title compound (13).

Example 14 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (14)

Step 1: Synthesis of 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate(14a)

3-Hydroxy-2,2-dimethylpropanoic acid (1.2 g, 10.3 mmol) and Cs₂CO₃ (3.4g, 10.4 mmol) were suspended in DMF (25 mL) at 23° C., then 2-bromoethylmethyl ether (1.0 mL, 10.4 mmol) was added. The resulting mixture wasstirred at 70° C. overnight. After cooling, the mixture was filteredthrough a pad of Celite®. The filtrate was diluted with EtOAc (150 mL),and the mixture washed with water (3×100 mL) and brine, then dried(Na₂SO₄), filtered and concentrated to leave a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:4 to 4:1) as eluent to provide the product (14a) (1.3g, crude weight) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 4.28 (t, J=4.8Hz, 2H), 3.62-3.55 (m, 4H), 3.38 (s, 3H), 2.65 (t, J=6.0 Hz, 1H), 1.21(s, 6H).

Step 2: Synthesis of 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.8 mmol) inEt₂O (7.0 mL) was cooled to −78° C. under an atmosphere of Ar. Asolution of 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (14a) (0.48g, 2.7 mmol) and pyridine (0.24 mL, 3.0 mmol) in Et₂O (1 mL) was addeddropwise to the sulfuryl chloride solution over the course of 11 min.The flask was rinsed with Et₂O (3×1 mL) which was also added to thereaction mixture. The mixture was stirred at −78° C. until completion(monitored by TLC, 30% EtOAc/hex, 30 min). The precipitate was filtered,and the filtrate was concentrated under vacuum to afford the product(14b) (0.5 g, 67%) as an oil, which was used directly in the next stepwithout further purification. Note: ¹H-NMR indicated desired productwith residue of pyridine and along with starting material.

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (14)

2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b) in the presence ofa base to provide the title compound (14).

Example 15 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-(oxetan-3-yloxy)-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (15)

Step 1: Synthesis of oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate (15a)

3-Hydroxy-2,2-dimethylpropanoic acid (4.7 g, 40 mmol) and Cs₂CO₃ (13.0g, 40 mmol) were suspended in DMF (100 mL) at 23° C., then 3-iodooxetane(7.4 g, 40 mmol) was added. The resulting mixture was stirred at 70° C.overnight. After cooling, the mixture was diluted with EtOAc (150 mL),and the mixture washed with water (3×100 mL) and brine, then dried(Na₂SO₄), filtered and concentrated to provide a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes as eluent to give the product (15a) (3.6 g, 51%) as anoil.

Step 2: Synthesis of oxetan-3-yl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.7 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate (15a) (0.46 g, 2.6 mmol)and pyridine (0.2 mL, 2.7 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over the course of 11 min. The flask wasrinsed with Et₂O (3×1 mL) which was also added to the reaction mixture.The mixture was stirred at −78° C. until completion (monitored by TLC,30% EtOAc/hex, 30 min). The precipitate was filtered, and the filtratewas concentrated under vacuum to afford the product (15b) (0.5 g, 69%)as an oil, which was used directly in the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 5.50-5.46 (m, 1H), 4.94-4.89(m, 2H), 4.65-4.60 (m, 2H), 4.52 (s, 2H), 1.72 (br. s, 1H), 1.36 (s,6H).

Step 3: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-(oxetan-3-yloxy)-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (15)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with oxetan-3-yl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b) in the presence ofa base to provide the title compound (15).

Example 16 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (16)

Step 1: Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (16a)

A solution of freshly distilled sulfuryl chloride (77 μL, 1.1 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (0.2 g, 1.0 mmol) andpyridine (85 μL, 1.1 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over 11 min. The flask was rinsed with Et₂O(3×1 mL) and the rinse added to the reaction. The mixture was stirred at−78° C. until completion (ca. 30 min; monitored by TLC, 30% EtOAc/hex).The precipitate was filtered, and the filtrate was concentrated undervacuum to afford the title compound as an oil, which was used directlyin the next step without purification. A second batch using 476 mg ofthe starting alcohol, afforded 600 mg of the product (16a)(approximately, 85% purity by ¹H-NMR).

Step 2: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (16)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (16a) in thepresence of a base to provide the title compound (16).

Example 17 Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclopentyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (17)

Step 1: Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclopropanecarboxylate (17a)

A solution of freshly distilled sulfuryl chloride (200 μL, 2.7 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclopentanecarboxylate (0.48 g, 2.7 mmol) andpyridine (222 μL, 2.7 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over 7 min. The flask was rinsed with Et₂O(2×1 mL) and both rinses were added to the reaction mixture. The mixturewas stirred at −78° C. for 1.5 h. The precipitate was filtered, and thefilter-cake washed with Et₂O (4 mL). The filtrate was concentrated undervacuum to afford the title compound (17a) as an oil, which was useddirectly in the next step without further purification.

Step 2: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclopentyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (17)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with ethyl1-(((chlorosulfonyl)oxy)methyl)cyclopropanecarboxylate (17a) in thepresence of a base to provide the title compound (17).

Example 182-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclobutyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (18)

Step 1: Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclobutanecarboxylate (18a)

A solution of freshly distilled sulfuryl chloride (451 μL, 6.2 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.1 mmol) andpyridine (500 μL, 6.2 mmol) in Et₂O (10 mL) was added dropwise to thesulfuryl chloride solution over the course of 11 min. The flask wasrinsed with Et₂O (3×1 mL), which was also added to the reaction mixture.The mixture was stirred at −78° C., which was allowed to warm to ambienttemp. within 4 h. The precipitate was filtered, and the filtrate wasconcentrated under vacuum to afford the title compound (18a) (1.2 g,76%) as an oil, which was used directly in the next step without furtherpurification. Note: ¹H-NMR indicated desired product, together withstarting material.

Step 2: Synthesis of2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-(((1-(ethoxycarbonyl)cyclobutyl)methoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicAcid (18)

2-((((E)-1-(2-Aminothiazol-4-yl)-2-(((2S,3S)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid (1) is reacted with ethyl1-(((chlorosulfonyl)oxy)methyl)cyclobutanecarboxylate (18a) in thepresence of a base to provide the title compound (18).

Example 19 Synthesis of (2S,3R)-benzyl2-((tert-butoxycarbonyl)amino)-3-hydroxybutanoate (19)

To a solution of Boc-L-threonine (15.0 g, 68.4 mmol) in DMF (465 mL) at0° C., were added NaHCO₃ (16.0 g, 190.2 mmol) and benzyl bromide (40.6mL, 342.1 mmol). After stirring overnight at 25° C., water was added andthe mixture was extracted with EtOAc. The organic layers were washedwith water and brine, and concentrated. The dried residue was purifiedwith flash chromatography over silica gel (0-60%, EA/Hex) to obtain thebenzyl ester product (19) (18.8 g, 89% yield) as a colorless oil. ¹H-NMR(300 MHz, CDCl₃) δ 7.43-7.29 (m, 5H), 5.35 (d, J=9.2 Hz, 1H), 5.32-5.11(m, 2H), 4.29 (d, J=9.4 Hz, 2H), 1.44 (s, 9H), 1.31-1.19 (m, 3H). LCMS(M+1)+: 310, calculated: 310.

Example 20 Synthesis of (2S,3S)-Benzyl3-azido-2-((tert-butoxycarbonyl)amino)butanoate (20)

To a solution of the benzyl ester of Example 19 (16.08 g, 51.98 mmol) inanhydrous DCM (90 mL) at −78° C. were sequentially added Tf₂O (10.94 mL,62.37 mmol) dropwise and 2,6-lutidine (7.87 mL, 67.57 mL) slowly. Afterstirring at the same temperature for 1.5 h and monitored with TLC(EtOAC/Hex 2:8), Bu₄NN₃ (36.38 g, 127.87 mmol) in anhydrous DCM (90 mL)was added slowly. After stirring for another 1 h at that temperature,the cooling bath was removed and the reaction was allowed to reach 25°C. for 1.5 h. A saturated aq. solution of NaHCO₃ was added, and theaqueous phase was extracted with EtOAc. The residue was purified withflash chromatography over silica gel (0-20%, EtOAc/Hex) to give thetitle compound (20) (15.24 g, 87% yield) as a colorless oil. ¹H-NMR (300MHz, CDCl₃) δ 7.61 (s, 1H), 7.36 (d, J=2.6 Hz, 4H), 5.29 (s, 1H),5.29-5.11 (m, 2H), 4.46 (d, J=8.5 Hz, 1H), 3.84 (d, J=8.1 Hz, 1H), 1.45(d, J=0.8 Hz, 9H), 1.34-1.16 (m, 3H). ¹³C NMR (75 MHz, cdcl3) δ: 169.5,155.1, 134.9, 128.7, 128.6, 128.5, 80.5, 67.6, 58.8, 57.5, 28.3, 28.3,15.4. LCMS (M+1)⁺: 335, calculated: 335.

Example 21 Synthesis of (2S,3S)-Benzyl3-amino-2-((tert-butoxycarbonyl)amino)butanoate (21)

To a solution of azido compound of Example 20 (2.11 g, 6.31 mmol) in THF(88 mL) was added Ph₃P (3.31 g, 12.62 mmol) and water (2.0 mL) and thereaction was heated to 60° C. overnight and monitored with TLC (in 50%EtOAc/Hex). When the reaction was completed, the solvent was removed invacuo and the residue was purified with flash chromatography over silicagel (0-80% EtOAc/Hex) to give the title compound (21) (1.84 g, 94%yield) as a colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.36 (t, J=1.5 Hz,5H), 7.26 (s, 1H), 5.30 (m, 1H), 5.28-5.10 (m, 2H), 4.32 (s, 1H), 3.30(s, 1H), 1.47 (s, 9H), 1.02 (d, J=6.7 Hz, 3H). LCMS (M+1)+: 309,calculated: 309.

Example 22 Synthesis of2-tert-Butoxycarbonylamino-3-(2-ethoxycarbonyl-2-methyl-propoxysulfonylamino)-butyricAcid Benzyl Ester (22)

To a solution of 3-amino-2-tert-butoxycarbonylamino-butyric acid benzylester (21) (2.83 g, 9.18 mmol, 1.0 eq) and triethylamine (6.40 mL, 45.9mmol, 5.0 eq) in dichloromethane (20 mL) was added dimethylaminepyridine(224 mg, 1.84 mmol, 0.20 eq) at 0° C.3-Chlorosulfonyloxy-2,2-dimethyl-propionic acid ethyl ester (3a) (4.49g, 18.4 mmol, 2.0 eq) in dichloromethane (5 mL) was added. The mixturewas kept in the same temperature for 1.5 h and warmed to roomtemperature for 2 h. The reaction was concentrated to dryness. Theresidue was diluted with ethyl acetate and washed with 10% citric acid.The organic phase was separated, dried over sodium sulfate, andconcentrated to dryness. The residue was purified by prep-HPLC to givethe title compound (22) (1.44 g, 30%) as a solid ¹H-NMR (300 MHz, CDCl₃)δ 7.37-7.27 (m, 5H), 6.03-5.96 (m, 1H), 5.52-5.46 (m, 1H), 5.18 (s, 2H),4.57-4.52 (m, 1H), 4.18-4.07 (m, 4H), 4.01-3.95 (m, 1H), 1.42 (s, 9H),1.33-1.22 (m, 9H), 1.16 (d, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.8, 169.6,134.7, 128.75, 128.70, 128.5, 81.0, 75.3, 67.9, 61.0, 57.7, 53.4, 52.8,42.6, 28.2, 22.1, 16.6, 14.1. LCMS (M+1)+: 517, calculated: 517.

Example 23 Synthesis of2-tert-Butoxycarbonylamino-3-(2-ethoxycarbonyl-2-methyl-propoxysulfonylamino)-butyricAcid (23)

To a solution of2-tert-butoxycarbonylamino-3-(2-ethoxycarbonyl-2-methyl-propoxysulfonylamino)-butyricacid benzyl ester (22) (1.32 g, 25.6 mmol, 1.0 eq) in ethyl acetate (20mL) was added Pd/C (132 mg). The suspension was degassed 3 times andrefilled with hydrogen. The mixture was stirred at room temperature for2h. The reaction mixture was filtered though a pad of Celite. Thefiltrate was concentrated to dryness, affording the title compound (23)(1.08 g, 100%). ¹H-NMR (300 MHz, CDCl₃) δ 6.23-1.18 (m, 1H), 5.68-5.63(m, 1H), 4.45-4.40 (m, 1H), 4.19-4.05 (m, 4H), 3.97-3.89 (m, 1H), 1.50(s, 9H), 1.39-1.22 (m, 12H). ¹³C NMR (75 MHz, d₆-acetone) δ 174.3,170.8, 156.1, 79.1, 74.8, 60.5, 59.8, 57.8, 44.2, 27.7, 21.5, 21.4,21.4, 16.1, 13.6, 13.6. LCMS (M+1)⁺: 427, calculated: 427.

Example 24 Synthesis of ethyl3-((((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate(24)

To a solution of2-tert-butoxycarbonylamino-3-(2-ethoxycarbonyl-2-methyl-propoxysulfonylamino)-butyricacid (23) (198 mg, 0.465 mmol, 1.0 eq) in DMF (2 mL) HATU (212 mg, 0.558mmol, 1.2 eq) and diisopropylethylamine (162 μL, 0.930 mmol, 2.0 eq)were added at 0° C. The reaction was stirred at 0° C. for 10 min andquenched with 10% citric acid. The mixture was purified by prep-HPLC togive the title compound (24) (104 mg, 55%). ¹H-NMR (300 MHz, d₆-acetone)δ 7.05-6.97 (m, 1H), 4.56-4.51 (m, 1H), 4.49-4.40 (m, 3H), 4.17 (q, 2H),1.55 (d, 3H), 1.42 (s, 9H), 1.33-1.22 (m, 9H). ¹³C NMR (75 MHz,d₆-acetone) δ 174.1, 164.1, 156.1, 79.9, 76.9, 64.6, 60.6, 59.1, 42.4,27.5, 21.3, 21.1, 16.7, 13.5. LCMS (M+1)+: 409, calculated: 409; (M-1)⁻407.

Example 25 Synthesis of3-(3-amino-2-methyl-4-oxo-azetidine-1-sulfonyloxy)-2,2-dimethyl-propionicAcid Ethyl Ester (25)

Ethyl3-((((2S,3S)-3-((tert-butoxycarbonyl)amino)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate(24) (12 mg) was treated with TFA/DCM (1:10, 1 mL) at 25° C. overnight.The reaction mixture was concentrated to dryness, affording thetrifluoroacetate salt of the title compound (25). LCMS (2M+1)⁺: 617,calculated: 617.

Example 26 Synthesis of ethyl3-((((2S,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate (26)

To the mixture of(Z)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)aceticacid (tert-butyl 1a) (459 mg, 1.39 mmol) in DCM (7.0 mL) was added DIPEA(557 μL, 3.20 mmol) and tritylchloride (855 mg, 3.07 mmol) at 25° C. andthe mixture was stirred for 3 h at 25° C. The solvent was removed undervacuum, and the residue was dissolved in EtOAc (20 mL) and washed withHCl (0.01N, 10 mL×3). The organic layer was then dried (Na₂SO₄),filtered and concentrated under vacuum. The residue was redissolved inEt₂O and the product precipitated out by addition of hexane. The product(26) was collected by filtration as an off-white solid. The filtrate wasconcentrated, dissolved in Et₂O, and precipitated with hexane to collectadditional product (370 mg). LCMS: m/z=571 (M+H)⁺

Example 27 Synthesis of ethyl3-((((2S,3S)-3-((E)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-(tert-butylamino)thiazol-4-yl)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate

A solution of(Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)aceticacid (26) (17.2 mg, 0.030 mmol) in DCM (0.5 mL) was treated with TCFH(12.6 mg, 0.045 mmol) and NMM (3.0 μL, 0.027 mmol). A solution of3-(3-amino-2-methyl-4-oxo-azetidine-1-sulfonyloxy)-2,2-dimethyl-propionicacid ethyl ester (25) (12.2 mg, 0.030 mmol) in DCM (0.15 mL) was addedto the reaction mixture at 25° C. and stirred for 2h. The reaction wasmonitored with LCMS. When the amine was consumed, the reaction wassubjected to purification by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 4:1) as eluent (two column purifications required)to provide the title compound (27) (2.8 mg, 11%). LCMS m/z=862 (M+H)⁺

Example 28 Synthesis of Tetrabutylammonium(2S,3S)-3-(((benzyloxy)carbonyl)amino)-2-methyl-4-oxoazetidine-1-sulfonate(28)

To a solution of (2S,3S)-3-amino-2-methyl-4-oxo-1-azetidinesulfonic acid(55.0 g, 305.2 mmol) in a mixture of EtOH (600 mL) and H₂O (300 mL) wasadded Et₃N (159.5 mL, 915.7 mmol) followed by benzyloxycarbonylN-succinimide (83.7 g, 335.8 mmol). The reaction mixture was stirred at25° C. for 16 h. Ethanol was removed under vacuum and the residue wasdiluted with H₂O (200 mL). The aqueous layer was extracted with EtOAc(2×100 mL). The EtOAc was discarded. Tetrabutyl ammonium hydroxide(207.9 g, 320.5 mmol) as 40% w/v in H₂O was added and the resultingaqueous layer was extracted with CHCl₃ (5×150 mL). The organic extractwas dried (MgSO₄) and concentrated to give the title compound (28) (160g, 94%) as a solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.38-7.31 (m, 5H), 4.31(d, J=7.2 Hz, 1H), 6.01 (s, 2H) 5.50 (s, 1H), 5.12 (s, 2H), 4.31 (d,J=7.2 Hz, 1H), 3.28-3.22 (m, 8H), 1.62-1.59 (m, 8H), 1.46-1.39 (m, 11H),1.01-0.96 (m, 12H); ¹³C-NMR (75 MHz, CDCl₃): δ 162.9, 155.7, 136.1,135.7, 128.5, 128.3, 128.2, 128.0, 67.0, 62.7, 59.2, 58.5, 23.9, 19.6,18.2, 13.7.

Example 29 Synthesis of Benzyl((2S,3S)-2-methyl-4-oxoazetidin-3-yl)carbamate (29)

(2S,3S)-3-(((Benzyloxy)carbonyl)amino)-2-methyl-4-oxoazetidine-1-sulfonatetetrabutylammonium salt (28) (131 g, 235.7 mmol) was dissolved in dryTHF (2.8 L) and H₂O (12.8 mL, 710.5 mmol), and the resulting solutionwas cooled in an ice bath. Trifluoroacetic acid (280 mL) was addeddropwise, and the mixture was stirred at 25° C. for 1.5 h. The reactionmixture was concentrated under vacuum, the residue was diluted with DCM(1.5 L), and then chilled with an ice bath. 10% Aqueous NaOH solutionwas added slowly until the mixture had a pH=8-9. The organic layer waswashed with H₂O, dried (MgSO₄), and concentrated under vacuum. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 1:0) to give the title compound (29) (30.1 g, 54%)as a solid. LC-MS: m/z=280.1 [M+HCO₂H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ7.38-7.31 (m, 5H), 6.01 (s, 1H) 5.50 (s, 1H), 5.12 (s, 2H), 4.31 (d,J=7.2 Hz, 1H), 3.74-3.71 (m, 1H), 1.42 (d, J=6 Hz, 3H); ¹³C-NMR (75 MHz,CDCl₃): δ 167.4, 155.9, 136.1, 67.2, 64.7, 54.0, 19.2.

Example 30 Synthesis of(2S,3R)-3-amino-2-(((benzyloxy)carbonyl)amino)butanoic acid HCl Salt(30)

Benzyl (((2S,3S)-2-methyl-4-oxoazetidin-3-yl)carbamate (29) (6.0 g, 25.6mmol) was dissolved in neat formic acid (50 mL). H₂O (50 mL) was addedand the resulting mixture was stirred at 25° C. for 18 h. The mixturewas concentrated under vacuum to give(2S,3R)-3-amino-2-(((benzyloxy)carbonyl)amino)butanoic formic acid saltas a solid. The formic acid salt was dissolved in MeCN (10 mL). 4N HClin dioxane (15 mL) was added and the resulting solution was concentratedto dryness under vacuum. Another portion of 4N HCl in dioxane (15 mL)was added and the mixture was stirred for 1 h at 25° C. to provide asolid. Et₂O (50 mL) was added and the solid was collected by filtrationto give the title compound (30) (6.8 g, 92%). LC-MS: m/z=253.3 [M+H]⁺;¹H-NMR (300 MHz, CD₃OD): δ 7.59 (d, J=8.7 Hz, 1H), 7.41-7.30 (m, 5H),5.15 (q, J=21 Hz, 2H), 4.68-4.64 (m, 1H), 3.88-3.84 (m, 1H), 1.25 (d,J=7.2 Hz, 3H); ¹³C-NMR (75 MHz, CD₃OD): δ 171.4, 159.1, 137.8, 129.5,129.1, 129.0, 68.3, 56.9, 49.9, 14.1.

Example 31 Synthesis of tert-butyl(2S,3R)-3-amino-2-(((benzyloxy)carbonyl)-amino)butanoate (31)

To a solution of (2S,3S)-3-amino-2-(((benzyloxy)carbonyl)amino)butanoicacid hydrochloride (30) (4.5 g, 15.5 mmol) in 1,4-dioxane (36 mL) at−10° C. was added dropwise concentrated H₂SO₄ (4.9 ml, 92.8 mmol). Thereaction mixture was placed in a dry ice-acetone bath and iso-butylene(36 g, 622.5 mmol) was added. The reaction vessel was capped, and thereaction mixture was stirred at 25° C. for 48 h. Iso-butylene wasremoved by passing nitrogen through the solution, and the mixture waspoured into a mixture of H₂O (150 mL) and saturated aqueous Na₂CO₃ (50mL). The aqueous layer was extracted with EtOAc (3×100 mL), and thecombined organic layers were washed with brine (50 mL), dried (MgSO₄),and concentrated under vacuum. The residue was purified by columnchromatography on silica gel using DCM/MeOH (1:0 to 9:1) to the titlecompound (31) (2.83 g, 59%) as a clear oil. LC-MS: m/z=309.6 [M+H]+;¹H-NMR (300 MHz, CDCl₃): δ 7.37-7.31 (m, 5H), 5.52 (d, J=6.9 Hz, 1H),5.11 (s, 2H), 4.28-4.24 (m, 1H), 3.33-3.30 (m, 1H), 1.46 (s, 9H), 1.05(d, J=6.9 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 170.0, 156.7, 136.3,128.6, 128.3, 128.2, 82.5, 67.1, 60.5, 49.5, 28.1, 18.9.

Example 32 Synthesis of tert-butyl(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)amino)butanoate(32)

To a solution of tert-butyl(2S,3R)-3-amino-2-(((benzyloxy)carbonyl)-amino)butanoate (29) (2.55 g,8.3 mmol) and N-methylmorpholine (2.73 mL, 24.8 mmol) in DCM (30 ml) at0° C. was added dropwise ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (3.65 g, 14.5 mmol).The mixture was stirred at 40° C. for 6 h. The solvent was concentratedunder vacuum and the residue was purified by column chromatography onsilica gel using Et₂O/hexanes (1:9 to 1:0) to give the title compound(32) (2 g, 47%) as a clear oil. LC-MS: m/z=516.9 [M+H]+; ¹H-NMR (300MHz, CDCl₃): δ 7.37-7.33 (m, 5H), 5.99 (d, J=7.8 Hz, 1H), 5.73 (d, J=5.7Hz, 1H), 5.13 (s, 2H), 4.49 (dd, J=7.2 Hz, 3.0 Hz, 1H), 4.20-4.13 (m,4H), 3.99-3.95 (m, 1H), 1.47 (s, 9H), 1.27-1.22 (m, 9H), 1.17 (d, J=6.6Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃): δ 174.9, 168.5, 135.9, 128.7, 128.5,128.4, 84.0, 75.4, 67.7, 61.2, 58.6, 53.0, 42.8, 28.0, 22.2, 16.5, 14.2.

Alternative Synthesis of(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)amino)butanoicAcid (32)

(2S,3S)-3-Amino-2-(((benzyloxy)carbonyl)amino)butanoic acidhydrochloride (30) (1.0 g, 3.5 mmol) and Et₃N (2.9 mL, 20.8 mmol) weresuspended into CDCl₃ (30 mL). The mixture was cooled in an ice bath andneat ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (1.31 g,5.2 mmol) was added to the cooled mixture. An aliquot was removed, andNMR analysis showed the absence of any benzyl protons. The reaction wasstirred at 0° C. for 3 h and allowed to warm and stirred for 16 h. Thesolution was extracted with saturated aqueous NH₄Cl (3×15 mL), brine(2×15 mL), then dried (Na₂SO₄), filtered and concentrated. NMR analysisof the crude product was complex and LCMS showed the presence of desiredm/z of 459 in negative mode. The crude material was dissolved into amixture of MeCN/H₂O (3:1) filtered through a 0.45-μm PTFE cartridge andpurified by preparative HPLC using MeCN/H₂O (1:9 to 9:1, no modifier) aseluent over a 20 min run time. Fractions were analyzed by LCMS and purefractions were pooled and freeze-dried to give the title compound (32)(330 mg, 21%) as an oil. LC-MS: m/z=459 [M−H]+; ¹H-NMR (300 MHz, CDCl₃):δ 7.27-7.34 (m, 5H), 5.98-6.05 (m, 2H), 5.11 (s, 2H), 4.50-4.55 (m, 1H),4.08-4.17 (m, 4H), 3.9-4.0 (m, 1H), 1.28 (d, J=7.2 Hz, 3H), 1.17-1.27(m, 9H); ¹³C-NMR (75 MHz, CDCl₃): δ 175.5, 172.0, 157.0, 135.8, 128.7,128.4, 128.2, 75.5, 67.8, 61.5, 58.2, 52.6, 42.8, 22.1, 17.5, 14.1.

Example 33 Synthesis of(2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)amino)butanoicAcid (33)

To a solution of tert-butyl(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-amino)butanoate(32) (115 mg, 0.22 mmol) and neat formic acid (0.7 mL) was stirred at25° C. for 5 h. The mixture was concentrated under vacuum, and theresidue was dissolved in a mixture of EtOAc (2 mL) and hexanes (1 mL).The organic layer was washed with H₂O (3×1 mL), dried (MgSO₄), andconcentrated. The material was dissolved in TFA for 30 min andevaporated to give the title compound (33) (97 mg, 96%) as a clear oil.

Example 34 Synthesis of ethyl3-((((2S,3S)-3-(((benzyloxy)carbonyl)amino)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate(34)

(2S,3R)-2-(((Benzyloxy)carbonyl)amino)-3-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)amino)butanoicacid (33) (197 mg, 0.4 mmol) and N,N-diisopropylethylamine (447 μL, 2.6mmol) were mixed with DMF (4.0 mL). The solution was cooled in an icebath and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (253 mg, 0.7 mmol) was added in one portion.The mixture was stirred at 0° C. for 35 min and the crude mixture wasdirectly purified by preparative-HPLC with MeCN/H₂O (1:9 to 9:1, nomodifier) over a 30 min run-time. Note: the product eluted ˜18 min. Thefractions containing the product were freeze-dried and the resulting oilwas analyzed by NMR to give a spectrum which conformed to the structure,as well as a small amount of DIPEA as an impurity. The impure solid wasdissolved in DCM and adsorbed onto silica gel (1.5 g) and purified bycolumn chromatography on silica gel (4 g cartridge) using EtOAc/hexanes(0:1 to 7:3) as eluent to give the title compound (34) (40 mg, 21%) asan oil. LC-MS: m/z=487 [M+HCO₂]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 7.27-7.40(m, 5H), 6.22 (br. d, 1H), 5.14 (s, 2H), 4.63 (dd, J=8.4, 9.0 Hz, 1H),4.56 (d, J=9.9 Hz, 1H), 4.10-4.20 (m, 4H), 1.62 (d, J=5.7 Hz, 1H),1.22-1.33 (m, 9H); ¹³C-NMR (100 MHz, CDCl₃): δ 175.9, 164.7, 155.5,135.9, 128.7, 128.5, 128.3, 77.3, 67.7, 64.6, 61.8, 61.0, 42.8, 22.2,21.7, 18.0, 14.0.

Example 35 Synthesis of ethyl3-((((2S,3S)-3-amino-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoateTFA Salt (35)

In an NMR tube, ethyl3-((((2S,3S)-3-(((benzyloxy)carbonyl)amino)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate(34) (5 mg) was dissolved into CD₃OD (0.65 mL) and the mixture wasflushed with nitrogen. Palladium on carbon (1 mg) was added to the NMRtube and the tube sealed with a rubber septum. A balloon filled withhydrogen was used to flush the NMR tube while alternating between vortexmixing and sonication. After 30 minutes the sample was analyzed by NMRand found to have no starting material present. After adding 1 drop ofTFA, the solution was filtered through a 0.2-μm PTFE frit, rinsed withmethanol (3×0.6 mL), and concentrated to give a film of the titlecompound (35). ¹H-NMR (300 MHz, acetone-d₆): δ 4.6 (d, J=6.0 Hz, 1H),4.12-4.20 (m, 2H), 4.10 (s, 2H), 3.76-3.79 (m, 1H), 1.33 (d, J=6.9 Hz,3H), 1.23-1.29 (m, 9H), 1.22-1.33 (m, 9H).

Example 36 Amide Coupling Reaction

The following diagrams illustrate reaction schemes for coupling asolution of(Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)aceticacid (26) with a3-(3-amino-2-methyl-4-oxo-azetidine-1-sulfonyloxy)-2,2-dimethyl-propionicacid ester (25).

Example 37 Synthesis of Aztreonam Derivatives

Other derivatives of aztreonam can be synthesized using the methodsdisclosed in Examples 29-33 and the chlorosulfonyls disclosed inExamples 38-98.

Example 38 Synthesis of 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (38)

A solution of distilled sulfuryl chloride (0.51 mL, 6.2 mmol) in Et₂O(10 mL) was cooled to −78° C. under nitrogen. A solution of2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (15a) (1.0 g, 5.68 mmol)and pyridine (0.46 mL, 5.68 mmol) in Et₂O (2.0 mL) was then addeddropwise over 1 h via a syringe. The reaction was stirred at −78° C. for1 h, and then the mixture was allowed to warm to room temperature andstirred for 2 h. After the mixture was filtered, the filtrate wasconcentrated under vacuum to give the product (38) as a colorless liquid(1.5 g, yield 96%). ¹H-NMR (300 MHz, CDCl₃): δ 4.40 (s, 2H), 4.29 (t,3H), 3.59 (t, 3H), 3.37 (s, 3H), 1.32 (s, 6H).

Example 39 Synthesis of hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (39)

Step 1: Synthesis of hexyl 3-hydroxy-2,2-dimethylpropanoate (39a)

A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-hexanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid, 1 mL) was heated to 80° C. and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum (high vacuum pumprequired) and the residue was then partitioned between EtOAc (100 mL)and saturated aqueous NaHCO₃ (100 mL). The aqueous phase was washed withH₂O (50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), and then driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum to providethe product as an oil. The product was difficult to purify using silicagel chromatography; and therefore the product was distilled under highvacuum at 47° C. to provide 4.92 g of the pure ester product (39a)(yield 61%). ¹H-NMR (300 MHz, CDCl₃) δ 4.10 (td, J=6.7, 1.3 Hz, 2H),3.55 (d, J=5.1 Hz, 2H), 2.42 (s, 1H), 1.64 (s, 1H), 1.72-1.56 (m, 1H),1.35 (s, 1H), 1.31 (s, 6H), 1.27-1.11 (m, 6H), 0.95-0.84 (m, 3H). MS(ESI) C₁₁H₂₂O₃=203 (M+1)⁺.

Step 2: Synthesis of hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (39b)

A solution of freshly distilled sulfuryl chloride (0.60 mL, 7.4 mmol) inEt₂O (10 mL) was cooled to −78° C. under an atmosphere of N₂. A solutionof hexyl 3-hydroxy-2,2-dimethylpropanoate (39a) (1.0 g, 4.94 mmol) andpyridine (0.48 mL, 5.93 mmol) in Et₂O (5 mL) was added dropwise to thesulfuryl chloride solution over the course of 20 min. The flask wasrinsed with Et₂O (3×1 mL) and the rinse added to the reaction mixture.The mixture was stirred at −78° C. until completion by TLC (30 min; 30%EA/hexane). The precipitate was filtered, and the filtrate wasconcentrated under vacuum to afford the crude product (39) as a solidfoam and was used in the next step without further purification. ¹H-NMR(300 MHz, CDCl₃): δ 4.50 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 1.69-1.60 (m,2H), 1.40-1.27 (m, 12H), 0.91-0.87 (m, 3H).

Example 40 Synthesis of heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (40)

Step 1: Synthesis of heptyl 3-hydroxy-2,2-dimethylpropanoate (40a).

A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-heptanol (70 mL) and concentrated sulfuric acid (1 mL) was heated to80° C. and stirred overnight. After allowing to cool, the mixture wasconcentrated under vacuum (high vacuum pump required) and the residuepartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (100mL). The aqueous phase was washed with H₂O (50 mL), saturated NaHCO₃ (50mL) and brine (50 mL), and then dried (Na₂SO₄), filtered andconcentrated under vacuum to provide the product as an oil. The productwas distilled under high vacuum at 65° C. to provide the title compound(40a) as an oil (6.7 g, 77% yield). ¹H-NMR (300 MHz, CDCl₃) δ 4.09 (td,J=6.7, 0.9 Hz, 2H), 3.55 (d, J=6.1 Hz, 2H), 2.43 (t, J=6.7 Hz, 1H), 1.60(d, J=22.8 Hz, 4H), 1.3-1.58 (m, 6H), 1.27-1.14 (m, 6H), 0.92-0.83 (m,3H).

Step 2: Synthesis of heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (40)

A solution of sulfuryl chloride (0.6 mL, 7.4 mmol) in Et₂O (15 mL) wascooled to −78° C. under an atmosphere of N₂. A solution of heptyl3-hydroxy-2,2-dimethylpropanoate (40a) (1.0 g, 4.94 mmol) and pyridine(479 μL, 5.93 mmol) in Et₂O (1 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×1 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion as monitored by TLC (30 min; 30%EA/hexane). The precipitate was filtered, and the filtrate wasconcentrated under vacuum to afford heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (40b) (1.37 g, yield92%). The mixture was stored at −78° C. and used in the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl₃) δ 4.50 (s, 2H),4.20-4.02 (m, 2H), 1.68 (m, 2H), 1.31 (d, J=3.1 Hz, 13H), 1.23 (s, 1H),0.95-0.83 (m, 3H).

Example 41 Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (41)

Step 1: Synthesis of ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (41a)

Diethyl cyclohexane-1,1-dicarboxylate (2.12 g, 9.29 mmol) was dissolvedin THF (50 mL) and to which was added LiAl(OtBu)₃ (5.9 g, 23.2 mmol) inportions. The reaction mixture was stirred at reflux overnight. Thereaction was cooled in an ice bath and treated carefully with 10% KHSO₄aq. solution (30 mL) with stirring for 10 min. The precipitate formedwas filtered out through a pad of Celite®. The filtrate was extractedwith EtOAc (3×40 mL) and the organic phase was combined and washed withbrine (50 mL), dried over NaSO₄, filtered and concentrated in vacuo. Theresidue was purified with CombiFlash (SiO₂) in 0-5% MeOH/DCM to obtainthe desired product (41a) as an oil (1.23 g, 71% yield). ¹H-NMR (300MHz, CDCl₃) δ 4.19 (qd, J=7.1, 0.8 Hz, 2H), 3.62 (d, J=6.4 Hz, 2H), 3.46(s, 1H), 2.00 (dt, J=11.5, 6.4 Hz, 4H), 1.57-1.22 (m, 9H).

Step 2: Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (41)

A solution of freshly distilled sulfuryl chloride (294 μL, 3.63 mmol) inEt₂O (10 mL) was cooled to −78° C. under an atmosphere of nitrogen. Asolution of ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (41a) (0.615g, 3.3 mmol) and pyridine (294 μL, 3.63 mmol) in Et₂O (6 mL) was addeddropwise to the sulfuryl chloride solution during 15 min. The flask wasrinsed with Et₂O (3×1 mL) and the rinse added to the reaction. Themixture was stirred at −78° C. until completion (ca. 30 min; monitoredby TLC, 30% EtOAc/hexane). The precipitate was filtered, and thefiltrate was concentrated under vacuum to afford the title compound (41)as an oil, 0.94 g in quantitative yield, which was used directly in thenext step without purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.52 (s, 2H),4.21 (q, J=7.1 Hz, 2H), 2.04 (s, 2H), 1.53-1.39 (m, 8H), 1.39-1.21 (m,3H).

Example 42 Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-((chlorosulfonyl)ox)-2,2-dimethylpropanoate (42)

Step 1: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-hydroxy-2,2-dimethylpropanoate (42a)

To a stirred solution of 3-hydroxy-2,2-dimethylpropanoic acid (4.0 g,33.9 mmol) and potassium carbonate (4.68 g, 33.9 mmol) in DMF (45 mL) at0° C. was added 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (5.03 g,33.9 mmol) in DMF (5 mL) dropwise over 1 h. The reaction was stirred atroom temperature overnight. The reaction mixture was diluted with EtOAcand washed with water and brine. The organic layer was dried withanhydrous Na₂SO₄, filtered, and concentrated under vacuum to give acrude residue. The residue was purified by silica gel columnchromatography using EtOAc/hexane (1:4 to 2:3) as eluent to give theproduct (42a) as a yellow liquid (1.6 g, yield 21%). ¹H-NMR (300 MHz,CDCl₃): δ 4.86 (s, 2H), 3.58 (s, 2H), 2.18 (s, 3H), 1.20 (s, 6H).

Step 2: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (42)

A solution of distilled sulfuryl chloride (0.61 mL, 7.53 mmol) in Et₂O(15 mL) was cooled to −78° C. under nitrogen. A solution of(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-hydroxy-2,2-dimethylpropanoate(42a) (1.48 g, 6.43 mmol) in Et₂O (1 mL) was added. Subsequently, asolution of pyridine (0.55 mL, 6.86 mmol) in Et₂O (1 mL) was added overa period of 1 h. The reaction was stirred at −78° C. for 1 h. After themixture was filtered, the filtrate was concentrated under vacuum to givethe product (42) as a yellow oil (1.6 g, yield 76%). ¹H-NMR (300 MHz,CDCl₃): δ 4.90 (s, 2H), 4.49 (s, 2H), 2.19 (s, 3H), 1.33 (s, 6H).

Example 43 Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropylBenzoate (43)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl benzoate (43a)

Benzoyl chloride (4.0 mL, 34.5 mmol) was added dropwise to a stirredsolution of 2,2-dimethylpropane-1,3-diol (10.8 g, 103.4 mmol), pyridine(5.8 mL, 71.6 mmol) and N,N-4-dimethylaminopyridine (840 mg, 6.9 mmol)in dichloromethane (207 mL) at ca. 0° C. The mixture was stirredovernight with gradual warming to room temperature, quenched by additionof 1N HCl (100 mL) at 0° C. and extracted twice with dichloromethane.The combined organic extracts were washed with saturated aqueous NaHCO₃(100 mL), brine (100 mL), dried (Na₂SO₄), filtered and the solventconcentrated under vacuum to leave a crude residue. The residue wassplit into two batches and purified by column chromatography on silicagel using EtOAc/hexanes (0:1 to 1:4) as eluent to give the product (43a)(5.95 g, 99%) as a colorless oil (note: oil dried under vacuum for 2days). LC-MS: m/z=209.0 [M+H]⁺. ¹H-NMR (300 MHz, CDCl₃): 8.05 (m, 2H),7.58 (m, 1H), 7.45 (m, 2H), 4.19 (s, 2H), 3.38 (d, J=6.3 Hz, 2H), 2.29(t, J=6.3 Hz, 1H), 1.02 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl Benzoate(43)

Reference is made to J. Am. Chem. Soc. 2006, 128, 1605-1610. A solutionof distilled sulfuryl chloride (1.2 mL, 15.8 mmol) in Et₂O (15 mL) wascooled to −78° C. under an atmosphere of argon. A solution of3-hydroxy-2,2-dimethylpropyl benzoate (43a) (3.0 g, 14.4 mmol) andpyridine (1.2 mL, 14.4 mmol) in Et₂O (3.0 mL) was then added dropwiseover 1 h via a syringe. The syringe was rinsed with Et₂O (3×1 mL), eachrinse being added to the reaction mixture. The acetone/CO₂ bath wasremoved, and the mixture allowed to warm to room temperature, thenstirred at room temperature for 4 h. TLC analysis (EtOAc/hexanes; 3:7)did not indicate complete reaction, so re-cooled to −78° C. and addedmore SO₂Cl₂ (0.1 mL), then allowed to warm to room temperature, andstirred for an additional 2 h. The mixture was filtered and the filtratewas concentrated under vacuum to give the product (43) (3.97 g, 89%) asan oil. ¹H-NMR (300 MHz, CDCl₃): 8.03 (m, 2H), 7.61-7.57 (m, 1H),7.49-7.44 (m, 2H), 4.41 (s, 2H), 4.18 (s, 2H), 1.16 (s, 6H).

Example 44 Synthesis of ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (44)

A solution of distilled sulfuryl chloride (0.55 mL, 7.5 mmol) in Et₂O(10 mL) was cooled to −78° C. under an atmosphere of argon. A solutionof ethyl 3-hydroxy-2,2-dimethylpropanoate (1.0 g, 6.8 mmol) and pyridine(0.55 mL, 6.8 mmol) in Et₂O (1.0 mL) was then added dropwise over 1 hvia a syringe. The syringe was rinsed with Et₂O (3×1 mL), each rinsebeing added to the reaction mixture. The acetone/CO₂ bath was removed,and the mixture was allowed to warm to room temperature, then stirred atroom temperature for 4 h. TLC analysis (EtOAc/hexanes; 3:7) did notindicate that the reaction was complete. The mixture was re-cooled to−78° C. and more SO₂Cl₂ (0.11 mL) was added, and the mixture allowed towarm to room temperature and stirred for an additional 2 h. The mixturewas filtered and the filtrate was concentrated under vacuum to give theproduct (44) (yield assumed quantitative). ¹H-NMR (300 MHz, CDCl₃): δ4.50 (s, 2H), 4.19 (q, J=6.9 Hz, 2H), 1.31 (s, 6H), 1.28 (t, J=6.9 Hz,3H).

Example 45 Synthesis of benzyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (45)

A solution of distilled sulfuryl chloride (0.77 mL, 10.6 mmol) in Et₂O(10 mL) was cooled to −78° C. under an atmosphere of argon. A solutionof ethyl 3-hydroxy-2,2-dimethylpropanoate (Sigma-Aldrich; 2.0 g, 9.6mmol) and pyridine (0.85 mL, 10.6 mmol) in Et₂O (2.0 mL) was then addeddropwise over 1 h via a syringe. The syringe was rinsed with Et₂O witheach rinse being added to the reaction mixture. The acetone/CO₂ bath wasremoved and the mixture allowed to warm to room temperature, thenstirred at room temperature for 30 min. TLC analysis (EtOAc/hexanes;3:7) did not indicate complete reaction, so re-cooled to −78° C. andadded more SO₂Cl₂ (0.07 mL), then allowed to warm to room temperatureand stirred for an additional 1 h. Et₂O (5 mL) was added and the mixturestirred for a few min, then filtered and the filtrate concentrated undervacuum to give the product (45) (2.19 g, 75%). ¹H-NMR (300 MHz, CDCl₃):δ 7.41-7.32 (m, 4H), 5.18 (s, 2H), 4.52 (s, 2H), 1.34 (s, 6H).

Example 46 Synthesis of Phenyl Sulfochloridate (46)

Reference is made to J. Am. Chem. Soc. 2013, 135, 10638-10641. Asolution of distilled sulfuryl chloride (2.6 mL, 35.1 mmol) in Et₂O (30mL) was cooled to −78° C. under an atmosphere of argon. A solution ofphenol (3.0 g, 31.9 mmol) in Et₂O (3.0 mL) and pyridine (2.6 mL, 31.9mmol) were then added concurrently, but from different syringes,dropwise over 1 h. The syringes were each rinsed with Et₂O and eachrinse was added to the reaction mixture. The mixture was allowed to warmto room temperature slowly and stirred at room temperature overnight.The mixture was filtered, and the filtrate concentrated under vacuum togive the product (4.65 g), contaminated with other products and phenolstarting material. The phenyl sulfochloridate product (46) was notpurified further and was used directly in the next step.

Example 47 Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylBenzoate (47)

Step 1: Synthesis of 2,2-dimethylbutane-1,4-diol (47a).

A solution of 2,2-dimethylsuccinic acid (10.0 g, 68.4 mmol) in THF (150mL) was added dropwise to a suspension of lithium aluminum hydride (8.3g, 219.0 mmol) in THF (80 mL) at 0° C. (ice bath). The mixture waswarmed to room temperature over 20 min and then heated at reflux for 1.5h. Upon completion (reaction monitored by TLC using MeOH/CH₂Cl₂ 5:95 aseluent) the reaction was quenched very carefully and dropwise by theaddition of water (10 mL), 3 M NaOH (15 mL), and water (20 mL). Themixture was stirred at room temperature for 20 min, and the solidsfiltered over a pad of Celite®. The filter cake was rinsed thoroughlywith THF. The filtrate was concentrated under vacuum giving a mixture ofthe title compound and unidentified by-products as a crude oil. The oilwas purified by column chromatography on silica gel using MeOH/CH₂Cl₂(0:1 to 1:9) as eluent to afford the product (47a) (4.649 g, 57%) as anoil. ¹H-NMR (300 MHz, CDCl₃): δ 4.11 (s, 2H), 3.66 (t, J=5.9 Hz, 2H),3.30 (s, 2H), 1.52 (t, J=5.6 Hz, 2H), 0.89 (s, 6H).

Step 2: Synthesis of 4-hydroxy-3,3-dimethylbutyl Benzoate (47b)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (47a) (0.30 g, 2.5mmol) in anhydrous dichloromethane (9 mL) was added benzoyl chloride(0.30 mL, 2.5 mmol), Et₃N (0.71 mL, 5.1 mmol), and a catalytic amount ofN,N-4-dimethylaminopyridine at 0° C. (ice bath). The mixture wasgradually warmed to room temperature and stirred overnight. After thestarting material was completely consumed (reaction monitored by TLCusing EtOAc/hexanes 2:8 as eluent), the reaction was quenched by theaddition of 1N HCl (20 mL) at 0° C. (ice bath), and the mixture wasextracted twice with dichloromethane. The combined organic layers werewashed with saturated aqueous NaHCO₃, brine, dried (Na₂SO₄), filteredand the solvent concentrated to yield a mixture, of at least twoproducts, as a clear and colorless oil. The oil was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 4:6) as eluentto give the product (47b) (0.29 g, 51%) as an oil (which was dried underhigh vacuum for 2 d). ¹H-NMR (300 MHz, CDCl₃): δ 8.04-8.01 (m, 2H),7.58-7.53 (m, 1H), 7.46-7.41 (m, 2H), 4.41 (t, J=7.4 Hz, 2H), 3.41 (s,2H), 1.78 (t, J=7.4 Hz, 2H), 1.70 (s, 1H), 0.99 (s, 6H).

Step 3: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl Benzoate(47)

A solution of freshly distilled sulfuryl chloride (0.11 mL, 1.5 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof 4-hydroxy-3,3-dimethylbutyl benzoate (47b) (0.28 g, 1.3 mmol) andpyridine (0.10 ml, 1.3 mmol) in Et₂O (2 mL) was added dropwise (over 1h) to the cooled solution. The mixture was warmed to room temperatureand stirred for 30 min (reaction was monitored by TLC usingEtOAc/hexanes 2:8 as eluent). The mixture was re-cooled to −78° C. andsulfuryl chloride (0.02 mL) was added. The mixture was allowed to warmto room temperature, and stirred for 30 min. Et₂O (5 mL) was added andthe mixture stirred for a few minutes. The mixture was filtered and thefiltrate concentrated under vacuum to give the product (47) (0.305 g,75%). ¹H-NMR (300 MHz, CDCl₃): δ 8.03 (d, J=8.1 Hz, 2H), 7.60-7.54 (m,1H), 7.47-7.42 (m, 2H), 4.44-4.38 (m, 2H), 4.29 (s, 2H), 1.89-1.85 (m,2H), 1.13 (s, 6H).

Example 48 Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylPropionate (48)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl Propionate (48a)

A solution of propionyl chloride (0.74 mL, 8.5 mmol) in anhydrousdichloromethane (5 mL) was added to a stirred solution of2,2-dimethylbutane-1,4-diol (47a) (1.00 g, 8.5 mmol), Et₃N (2.4 mL, 16.9mmol), and 4-N,N-dimethylaminopyridine (52 mg) in anhydrousdichloromethane (20 mL) at −78° C. under an atmosphere of argon. Themixture was stirred for 10 min and then allowed to warm to roomtemperature, stirred at room temperature for 1 h, then re-cooled to −78°C., and allowed to warm to room temperature slowly by allowing themixture to stay in the cold bath and letting the dry ice sublime(recommended to allow warming to room temperature from −78° C. afteraddition of all the reagents). After the starting material wascompletely consumed (TLC 50% EtOAc/hexanes), the reaction was quenchedby the addition of 0.5 N HCl (10 mL) at 0° C. The organic and aqueouslayers were partitioned, and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃ (20 mL), brine (20 mL), then dried (Na₂SO₄),filtered and the solvent concentrated under vacuum to leave a crude oil.The oil was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 4:1) as eluent to give the product (48a) (463 mg,22%) as an oil, contaminated with significant EtOAc solvent residues.¹H-NMR (300 MHz, CDCl₃): δ 4.14 (t, J=7.4 Hz, 2H), 3.32 (s, 2H), 2.30(q, J=7.6 Hz, 2H), 1.88 (s, 1H), 1.61 (t, J=7.7 Hz, 2H), 1.13 (t, J=7.5Hz, 3H), 0.91 (fd, J=1.2 Hz, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylPropionate (48)

A solution of freshly distilled sulfuryl chloride (0.15 mL, 2.0 mmol) inEt₂O (3.5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl propionate (48a) (73% purity,the remainder being EtOAc; 441 mg, 1.8 mmol) and pyridine (0.15 mL, 1.8mmol) in Et₂O (2.5 mL) was added dropwise over 1 h to the cooledsolution. The mixture was allowed to warm to room temperature and wasstirred for 30 min (monitored by TLC, 30% EtOAc/hexanes), re-cooled to−78° C. and sulfuryl chloride (0.03 mL) and pyridine (0.03 mL) wasadded, warmed to room temperature, and stirred for 30 min. Again, themixture was re-cooled to −78° C. and another portion of sulfurylchloride (0.15 mL) was added. The mixture was allowed to warm to roomtemperature, and stirred for 30 min. Et₂O (5 mL) was added and themixture stirred for a few min. The mixture was filtered and the filtratewas concentrated under vacuum to give the product (48) (401 mg, 79%).¹H-NMR: (300 MHz, CDCl₃): 4.22 (s, 2H), 4.14 (t, J=6.8 Hz, 2H), 2.30 (q,J=7.6 Hz, 2H), 1.70 (t, J=6.8 Hz, 2H), 1.11 (t, J=7.7 Hz, 3H), 1.05 (s,6H).

Example 49 Synthesis of benzyl(4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl) adipate (49)

Step 1: Synthesis of Benzyl (Perfluorophenyl) Adipate (49a)

To a stirring solution of adipic acid monobenzyl ester (1.03 g, 4.3mmol) and pentafluorophenol (0.87 g, 4.7 mmol) in EtOAc (18.7 mL) at 0°C. was added N,N′-dicyclohexylcarbodiimide (0.97 g, 4.7 mmol). Themixture was allowed to warm to room temperature and then stirredovernight. The resulting solid was removed by vacuum filtration througha pad of Celite®. The filter cake was washed with EtOAc. The filtratewas dry-loaded on to silica gel and purified by column chromatography onsilica gel using EtOAc/hexanes (0:1 to 4:6) as eluent, to give theproduct (49a) (1.59 g, 93%) as a solid. ¹H-NMR (300 MHz, CDCl₃): δ7.37-7.35 (m, 5H), 5.13 (s, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.44 (t, J=6.5Hz, 2H), 1.82-1.78 (m, 4H).

Step 2: Synthesis of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (49b)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (47a) (0.22 g, 1.8mmol) in anhydrous dichloromethane (4 mL) at ca. 0° C. (ice bath), underan atmosphere of argon, was added benzyl (perfluorophenyl) adipate (49a)(0.36 g, 0.9 mmol), Et₃N (0.25 mL, 1.8 mmol), and a catalytic amount of4-N,N-dimethylaminopyridine (small unweighed amount). The mixture wasgradually warmed to room temperature, and then at room temperatureovernight. The mixture was dry-loaded on to silica gel and purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 3:7) aseluent to give the product contaminated with regio-isomeric product.This mixture was re-purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 3:7) as eluent to give pure product (49b)(113 mg 38%). ¹H-NMR (300 MHz, CDCl₃): 7.36-7.34 (m, 5H), 5.11 (s, 2H),4.14 (t, J=7.2 Hz, 2H), 3.34 (d, J=5.7 Hz, 2H), 2.38-2.31 (m, 4H),1.68-1.59 (m, 6H), 0.92 (s, 6H). The reaction could be repeated to givelarger amounts of material.

Step 3: Synthesis of benzyl (4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl)adipate (49)

A solution of freshly distilled sulfuryl chloride (0.12 ml, 1.6 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (49b) (446 mg,1.3 mmol) and pyridine (0.11 mL, 1.3 mmol) in Et₂O (3.5 mL) was addeddropwise over 1 h to the cooled solution. The mixture was allowed towarm to room temperature and was stirred for 30 min (monitored by TLC,30% EA/hex). The reaction was not complete, so the mixture was recooledto −78° C., then sulfuryl chloride (0.05 mL) and pyridine (0.05 mL) wereadded. The mixture was allowed to warm to room temperature, and stirredfor 30 min. Et₂O (5 mL) was added, and the mixture was stirred for a fewmins. The mixture was filtered and the filtrate was concentrated undervacuum to give the product (49) (446 mg, 77%). ¹H-NMR (300 MHz, CDCl₃):δ 7.39-7.29 (m, 5H), 5.11 (s, 2H), 4.22 (s, 2H), 4.15 (t, J=6.8 Hz, 2H),2.40-2.29 (m, 4H), 1.73-1.59 (m, 6H), 1.06 (s, 6H).

Example 50 Synthesis of methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (50)

A solution of freshly distilled sulfuryl chloride (3.3 mL, 45.4 mmol) inEt₂O (45 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof methyl 2,2-dimethyl-3-hydroxypropionate (3.0 g, 22.7 mmol) andpyridine (2.2 mL, 27.2 mmol) in Et₂O (20 mL) was added dropwise to thesulfuryl chloride solution over 30 min. The flask was rinsed with Et₂O(3×5 mL) and the rinse was added to the reaction mixture. The mixturewas stirred at −78° C. until completion (monitored by TLC, 30% EA/hex,30 min). The precipitate was filtered, and the filtrate was concentratedunder vacuum to afford methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (50) (5.6 g, 70% yield).The mixture was stored at −78° C. and was used immediately for the nextstep without further purification. ¹H-NMR (300 MHz, CDCl₃) δ 4.50 (s,2H), 3.74 (s, 3H), 1.31 (s, 6H).

Example 51 Synthesis of Isopropyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (48)

Step 1: Synthesis of isopropyl 3-hydroxy-2,2-dimethylpropanoate (51a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),isopropanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to reflux and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum and the residuepartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (100mL). The aqueous mixture was washed with H₂O (50 mL), saturated NaHCO₃(50 mL) and brine (50 mL), then dried (Na₂SO₄), filtered andconcentrated under vacuum to leave provide the product as an oil. Theproduct (51a) was used directly in the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 5.08-4.95 (m, 1H), 3.53 (fd,J=1.8 Hz, 2H), 2.49 (s, 1H), 1.25 (fd, J=2.4 Hz, 3H), 1.22 (fd, J=2.4Hz, 3H), 1.17 (s, 3H), 1.16 (s, 3H).

Step 2: Synthesis of isopropyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (51)

A solution of sulfuryl chloride (2.7 mL, 37.5 mmol) in Et₂O (45 mL) wascooled to −78° C. under an atmosphere of Ar. A solution of isopropyl3-hydroxy-2,2-dimethylpropanoate (51a) (3.0 g, 18.7 mmol) and pyridine(1.82 mL, 22.5 mmol) in Et₂O (20 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion by TLC (30 min; 30% EA/hex). Theprecipitate was filtered, and the filtrate was concentrated under vacuumto afford isopropyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (51)(4.1 g, 85% yield). The mixture was stored at −78° C. and was usedimmediately for the next step without further purification. ¹H-NMR (300MHz, CDCl₃): δ 5.10-4.98 (m, 1H), 4.49 (s, 2H), 1.29 (s, 6H), 1.26 (s,3H), 1.24 (s, 3H).

Example 52 Synthesis of Hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (52)

Step 1: Synthesis of hexyl 3-hydroxy-2,2-dimethylpropanoate (52a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-hexanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to 80° C. and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum (high vacuum pumprequired) and the residue partitioned between EtOAc (100 mL) andsaturated aqueous NaHCO₃ (100 mL). The aqueous mixture was washed withH₂O (50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), then dried(Na₂SO₄), filtered and concentrated under vacuum to provide the product(52a) as an oil. The product (49a) was used directly in the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.04-3.98 (m,21H), 3.47-3.45 (m, 2H), 2.26 (s, 1H), 1.58-1.32 (m, 21H), 1.32-1.23 (m,6H), 1.12 (s, 3H), 1.11 (s, 3H).

Step 2: Synthesis of hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (52)

A solution of sulfuryl chloride (2.1 mL, 29.7 mmol) in Et₂O (40 mL) wascooled to −78° C. under an atmosphere of argon. A solution of hexyl3-hydroxy-2,2-dimethylpropanoate (52a) (3.0 g, 14.8 mmol) and pyridine(1.4 mL, 17.8 mmol) in Et₂O (15 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion by TLC (30 min; 30% EA/hex). Theprecipitate was filtered, and the filtrate was concentrated under vacuumto afford the product (52) (3.7 g, 83% yield). The mixture was stored at−78° C. and was used immediately for the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): 4.50 (s, 2H), 4.13 (t, J=6.8 Hz,2H), 1.69-1.60 (m, 2H), 1.40-1.27 (m, 12H), 0.91-0.87 (m, 3H).

Example 53 Synthesis of heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (53)

Step 1: Synthesis of heptyl 3-hydroxy-2,2-dimethylpropanoate (53a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-heptanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to 80° C. and stirred overnight. After allowingthe mixture to cool, the mixture was concentrated under vacuum (highvacuum pump required) and the residue partitioned between EtOAc (100 mL)and saturated aqueous NaHCO₃ (100 mL). The aqueous was washing with H₂O(50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), then dried(Na₂SO₄), filtered and concentrated under vacuum to provide the product(53a) as an oil. The product was used directly in the next step withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.31 (t, J=6.5 Hz, 2H),3.77 (s, 2H), 1.87-1.81 (m, 2H), 1.53-1.50 (m, 8H), 1.41 (s, 6H),1.12-1.08 (m, 3H).

Step 2: Synthesis of heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (53)

A solution of sulfuryl chloride (2.0 mL, 27.7 mmol) in Et₂O (40 mL) wascooled to −78° C. under an atmosphere of argon. A solution of heptyl3-hydroxy-2,2-dimethylpropanoate (53a) (3.0 g, 13.9 mmol) and pyridine(1.4 mL, 16.6 mmol) in Et₂O (15 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion as monitored by TLC (30 min; 30%EA/hex). The precipitate was filtered, and the filtrate was concentratedunder vacuum to afford heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (53) (3.3 g, 75%). Themixture was stored at −78° C. and was used immediately for the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.46 (s, 2H),4.11-4.00 (m, 2H), 1.64-1.55 (m, 2H), 1.26-1.24 (m, 8H), 0.85-0.81 (m,3H).

Example 54 Synthesis of Tert-Butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (54)

Step 1 and Step 2: Synthesis of tert-butyl3-hydroxy-2,2-dimethylpropanoate (54a)

The compound was synthesized in accordance with PCT InternationalApplication Publication No. WO 2007116922. Sodium hydride (60% inmineral oil; 2.0 g) was added to a cooled solution of tert-butyl methylmalonate (4 g) in THF (100 mL) at 0° C. under an atmosphere of Ar. Themixture was stirred at 0° C. for 10 min. MeI (3.2 mL) was added to themixture and the stirring was continued for 3 h (by this time the mixturewas at room temperature). Brine and EtOAc were added to the mixture, andthe organic layer was separated, dried (Na₂SO₄), filtered andconcentrated under vacuum to give the product (ca. 4.5 g), which wasused directly in the next step.

Solid lithium tri-tert-butoxy-aluminohydride (7.1 g, 28 mmol) was addedportion-wise over 15 min to a solution of tert-butyl methyl2,2-dimethyl-malonate (2.2 g) in THF (100 mL) under an atmosphere of Ar.The mixture was then heated to reflux and stirred overnight. Aftercooling to room temperature, a saturated solution of NH₄Cl and EtOAcwere added, and the aqueous and organic layers were separated. Theorganic layer was washed with H₂O and brine, then dried (Na₂SO₄),filtered and concentrated under vacuum to provide a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 3:7) as eluent to give the product (54a) (900 mg)as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 3.50 (d, J=5.1 Hz, 2H), 2.53 (t,J=6.5 Hz, 1H), 1.45 (s, 9H), 1.14 (s, 6H)

Step 3: Synthesis of tert-butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (54)

A solution of sulfuryl chloride (0.31 mL, 4.2 mmol) in Et₂O (6 mL) wascooled to −78° C. under an atmosphere of Ar. A solution of tert-butyl3-hydroxy-2,2-dimethylpropanoate (54a) (0.49 g, 2.8 mmol) and pyridine(0.25 ml, 3.1 mmol) in Et₂O (6 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The mixture was stirred at−78° C. for 90 min and allowed to warm to 23° C. after TLC revealed thatthe reaction had not proceeded to completion (10% EtOAc/hexanes). Themixture was re-cooled to −78° C. and an additional 1 equivalent ofsulfuryl chloride was added, stirred for 10 min, and the mixture allowedto warm to 23° C. (note: the mixture was allowed to stir for a total of1 h after the addition and during the warming period). The precipitatewas filtered, and the filtrate was concentrated under vacuum to givetert-butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (54) (961 mg,yield assumed quantitative) as a clear, oil. ¹H-NMR (300 MHz, CDCl₃): δ4.46 (fd, J=1.5 Hz, 2H), 1.47 (fd, J=1.2 Hz, 9H), 1.27 (s, 6H).

Example 55 Synthesis of 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (55)

Step 1: Synthesis of 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate(55a)

3-Hydroxy-2,2-dimethylpropanoic acid (1.2 g, 10.3 mmol) and Cs₂CO₃ (3.4g, 10.4 mmol) were suspended in DMF (25 mL) at 23° C., then 2-bromoethylmethyl ether (1.0 mL, 10.4 mmol) was added. The resulting mixture wasstirred at 70° C. overnight. After cooling, the mixture was filteredthrough a pad of Celite®. The filtrate was diluted with EtOAc (150 mL),and the mixture washed with water (3×100 mL) and brine, then dried(Na₂SO₄), filtered and concentrated to leave a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:4 to 4:1) as eluent to provide the product (55a) (1.3g, crude weight) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 4.28 (t, J=4.8Hz, 2H), 3.62-3.55 (m, 4H), 3.38 (s, 3H), 2.65 (t, J=6.0 Hz, 1H), 1.21(s, 6H).

Step 2: Synthesis of 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (55)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.8 mmol) inEt₂O (7.0 mL) was cooled to −78° C. under an atmosphere of Ar. Asolution of 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (55a) (0.48g, 2.7 mmol) and pyridine (0.24 mL, 3.0 mmol) in Et₂O (1 mL) was addeddropwise to the sulfuryl chloride solution over the course of 11 min.The flask was rinsed with Et₂O (3×1 mL) which was also added to thereaction mixture. The mixture was stirred at −78° C. until completion(monitored by TLC, 30% EtOAc/hex, 30 min). The precipitate was filtered,and the filtrate was concentrated under vacuum to afford the product(55) (0.5 g, 67%) as an oil, which was used directly in the next stepwithout further purification. Note: ¹H-NMR indicated desired productwith residue of pyridine and along with starting material.

Example 56 Synthesis of oxetan-3-yl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (56)

Step 1: Synthesis of oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate (56a)

3-Hydroxy-2,2-dimethylpropanoic acid (4.7 g, 40 mmol) and Cs₂CO₃ (13.0g, 40 mmol) were suspended in DMF (100 mL) at 23° C., then 3-iodooxetane(7.4 g, 40 mmol) was added. The resulting mixture was stirred at 70° C.overnight. After cooling, the mixture was diluted with EtOAc (150 mL),and the mixture washed with water (3×100 mL) and brine, then dried(Na₂SO₄), filtered and concentrated to provide a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes as eluent to give the product (56a) (3.6 g, 51%) as anoil.

Step 2: Synthesis of oxetan-3-yl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (56)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.7 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate (56a) (0.46 g, 2.6 mmol)and pyridine (0.2 mL, 2.7 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over the course of 11 min. The flask wasrinsed with Et₂O (3×1 mL) which was also added to the reaction mixture.The mixture was stirred at −78° C. until completion (monitored by TLC,30% EtOAc/hex, 30 min). The precipitate was filtered, and the filtratewas concentrated under vacuum to afford the product (56) (0.5 g, 69%) asan oil, which was used directly in the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 5.50-5.46 (m, 1H), 4.94-4.89(m, 2H), 4.65-4.60 (m, 2H), 4.52 (s, 2H), 1.72 (br. s, 1H), 1.36 (s,6H).

Example 57 Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (57)

A solution of freshly distilled sulfuryl chloride (77 μL, 1.1 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (0.2 g, 1.0 mmol) andpyridine (85 μL, 1.1 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over 11 min. The flask was rinsed with Et₂O(3×1 mL) and the rinse added to the reaction. The mixture was stirred at−78° C. until completion (ca. 30 min; monitored by TLC, 30% EtOAc/hex).The precipitate was filtered, and the filtrate was concentrated undervacuum to afford the title compound (57) as an oil, which was useddirectly in the next step without purification. A second batch using 476mg of the starting alcohol, afforded 600 mg of the product (57)(approximately, 85% purity by ¹H-NMR).

Example 58 Step 1: Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclopentane-1-carboxylate (58)

A solution of freshly distilled sulfuryl chloride (200 μL, 2.7 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclopentanecarboxylate (0.48 g, 2.7 mmol) andpyridine (222 μL, 2.7 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over 7 min. The flask was rinsed with Et₂O(2×1 mL) and both rinses were added to the reaction mixture. The mixturewas stirred at −78° C. for 1.5 h. The precipitate was filtered, and thefilter-cake washed with Et₂O (4 mL). The filtrate was concentrated undervacuum to afford the title compound (58) as an oil, which was useddirectly in the next step without further purification.

Example 59 Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclobutanecarboxylate (59)

A solution of freshly distilled sulfuryl chloride (451 μL, 6.2 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.1 mmol) andpyridine (500 μL, 6.2 mmol) in Et₂O (10 mL) was added dropwise to thesulfuryl chloride solution over the course of 11 min. The flask wasrinsed with Et₂O (3×1 mL), which was also added to the reaction mixture.The mixture was stirred at −78° C., which was allowed to warm to ambienttemp. within 4 h. The precipitate was filtered, and the filtrate wasconcentrated under vacuum to afford the title compound (59) (1.2 g, 76%)as an oil, which was used directly in the next step without furtherpurification. Note: ¹H-NMR indicated desired product (19a), togetherwith starting material.

Example 60 Synthesis of Ethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (60)

Step 1: Synthesis of ethyl 5-hydroxy-4,4-dimethylpentanoate (60a)

To a suspension of sodium 5-ethoxy-2,2-dimethyl-5-oxopentanoate (3.77 g,17.9 mmol) in a mixture of tetrahydrofuran (39 mL) and DMF (13 mL) wasadded a solution of isopropyl chloroformate, 1.0M in toluene (27.0 mL,27.0 mmol) at 0° C. The mixture was stirred at 0° C. for 10 min, andthen allowed to warm to room temperature, and stirred for 2 h. Thesolution was cooled to 0° C. and sodium borohydride (1.21 g, 35.9 mmol)was added. The mixture was stirred for 20 min then methanol (6.5 mL) wasadded to the solution. After 10 min of stirring, ethyl acetate (25 mL)modified with a few drops of triethylamine and a saturated aqueoussolution of NH₄Cl (25 mL) were added. The layers were separated, and theaqueous layer was extracted with EtOAc (2×40 mL). The combined organiclayers were washed with brine, dried (MgSO₄), filtered and the filtratewas concentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes modified with 0.1% TEA(5:95 to 4:6) to give the product (60a) (2.01 g, 64% crude) as acolorless oil. One drop of triethylamine was added to the product tosuppress lactonization.

Step 2: Synthesis of Ethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (60)

A solution of sulfuryl chloride (0.64 mL, 8.7 mmol) in Et₂O (10 mL) wascooled to −78° C. under an atmosphere of nitrogen. A solution of ethyl5-hydroxy-4,4-dimethylpentanoate (60a) (0.76 g, 4.4 mmol) and pyridine(0.39 mL, 4.8 mmol) in Et₂O (10 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The syringe was rinsed withEt₂O (3×1 mL) and this was also added to the mixture. The mixture wasstirred at −78° C. for 1.5 h, additional pyridine (0.9 equiv.) wasadded, and the mixture was filtered through a pad of Celite®. Thefiltrate was concentrated under vacuum to give the product (60) (0.897g) as a colorless oil. This was used in the next step without furtherpurification.

Example 61 Synthesis of hexyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (61)

Step 1: Synthesis of sodium-5-(hexyloxy)-2,2-dimethyl-5-oxopentanoate(61a)

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in1-hexanol (50 mL) was added a solution of sodium hexan-1-olae (5.4 g,43.5 rnmol) in 1-hexanol. After 20 h of stirring, the solvent wasevaporated and the resulting solid was suspended in diethyl ether (80mL). The mixture was filtered and the solid was washed with diethylether (2×40 mL). The solid was dried under high vacuum to afford theproduct (61a) (3.84 g, 41%) as a solid. ¹H-NMR (300 MHz, D₂O): δ 4.14(t, J=6.5 Hz, 2H), 2.38-2.33 (m, 2H), 1.82-1.77 (m, 2H), 1.75-1.63 (m,2H), 1.43-1.28 (m, 6H), 1.12 (s, 6H), 0.92-0.88 (m, 3H). The spectrumrevealed that the product was contaminated with a small amount of anunidentified substance.

Step 2: Synthesis of hexyl 5-hydroxy-4,4-dimethylpentanoate (61b)

To a suspension of sodium 5-(hexyloxy)-2,2-dimethyl-5-oxopentanoate(61a) (3.84 g, 14.4 mmol) in a mixture of THF (31 mL) and DMF (10 mL)was added isopropyl chloroformate, 1.0M in toluene (21.6 mL, 21.6 mmol)at 0° C. and the mixture was stirred for 10 min. After 3.3 h of stirringat room temperature, the solution was cooled to 0° C. and sodiumborohydride (0.98 g, 28.8 mmol) was added. The mixture was stirred for20 min and MeOH (5.2 mL) was added to the solution (reaction monitoredby TLC using 2:8 ethyl acetate/hexanes as eluent). After 15 min, a fewdrops of triethylamine were added. After another 15 min of stirring,ethyl acetate (25 mL) and a solution of saturated aqueous NH₄Cl wasadded (25 mL). The organic and aqueous layers were separated, and theaqueous layer was extracted with EtOAc (2×40 mL). The combined organiclayers were washed with brine, dried (MgSO₄), and filtered, and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes modified with 0.1% Et₃N(5:95 to 3:7) to give the product (61b) (2.16 g, 65%) as a colorlessoil. One drop of Et₃N was added to suppress lactonization.

Step 3: Synthesis of hexyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (61)

A solution of sulfuryl chloride (0.38 mL, 5.2 mmol) in Et₂O (8.5 mL) wascooled to −78° C. under a nitrogen atmosphere. A solution of hexyl5-hydroxy-4,4-dimethylpentanoate (61b) (0.60 g, 2.6 mmol) and pyridine(0.42 mL, 5.2 mmol) in Et₂O (8.5 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The syringe was rinsed withEt₂O (3×1 mL) and the rinse was also added to the mixture. The mixturewas stirred for 4.5 h (reaction monitored by TLC using 2:8 EtOAc/hexanesas eluent). The solids were filtered off and the solvent wasconcentrated in vacuo to give the product (61) as a colorless oil with aquantitative yield. To this was added 3 mL of THF and the solution wasstored at −78° C. This was used in the next step without furtherpurification.

Example 62 Synthesis of Heptyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (62)

Step 1: Synthesis of sodium 5-(heptyloxy)-2,2-dimethyl-5-oxopentanoate(62a)

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in1-heptanol (40 mL) was added a solution of sodium heptan-1-olate (6.01g, 43.5 mmol) in 1-heptanol (30 mL). After stirring overnight thesolvent was evaporated and the resulting solid was suspended in Et₂O (80mL). The mixture was filtered and the solid was washed with Et₂O (2×40mL). The solid was dried under high vacuum to afford the product (62a)(7.89 g, 80%) as a solid. ¹H-NMR (300 MHz, D₂O): δ 4.14 (t, J=6.5 Hz,2H), 2.36-2.32 (m, 2H), 1.82-1.77 (m, 2H), 1.74-1.63 (m, 2H), 1.40-1.31(m, 8H), 1.11 (s, 6H), 0.92-0.87 (m, 3H). The spectrum revealed that theproduct was contaminated with a small amount of an unidentifiedsubstance.

Step 2: Synthesis of heptyl 5-hydroxy-4,4-dimethylpentanoate (62b)

To a suspension of sodium 5-(heptyloxy)-2,2-dimethyl-5-oxopentanoate(62a) (7.89 g, 28.1 mmol) in a mixture of THF (61 mL) and DMF (20 mL)was added isopropyl chloroformate, 1.0M in toluene (42.2 mL, 42.2 mmol)at 0° C. and the mixture was stirred for 10 min. After 4 h of stirringat room temperature, the suspension was cooled to 0° C. and sodiumborohydride (1.9 g, 56.3 mmol) was added. The mixture was stirred for 20min and then MeOH (10 mL) was added to the solution (reaction monitoredby TLC using 2:8 ethyl acetate/hexanes). After 30 min of stirring, EtOAc(50 mL), a few drops of Et₃N, and a saturated aqueous solution of NH₄Clwere added (50 mL). The aqueous and organic layers were separated, andthe aqueous layer was extracted with EtOAc (2×80 mL). The combinedorganic layers were washed with brine (80 mL), and the filtrate wasconcentrated in vacuo. The residual solution was washed with H₂O (3×100mL), brine (100 mL), and dried (Na₂SO₄), and concentrated. During allextractions, several drops of Et₃N were added to the organic layer tosuppress lactonization. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes modified with 0.1% Et₃N(0:1 to 3:7) as eluent to give the product (62a) (3.35 g, 49% crude) asa colorless oil.

Step 3: Synthesis of heptyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (62)

A solution of sulfuryl chloride (0.60 mL, 8.2 mmol) in Et₂O (13 mL) wascooled to −78° C. under a nitrogen atmosphere. A solution of heptyl5-hydroxy-4,4-dimethylpentanoate (62a) (1.0 g, 4.1 mmol) and pyridine(0.66 mL, 8.2 mmol) in Et₂O (13 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The syringe was rinsed withdiethyl ether (3×1 mL) and this was also added to the mixture. Themixture was stirred for 4.5 h (reaction monitored by TLC using 2:8 ethylacetate/hexanes as eluent). The solids were filtered-off, and thefiltrate concentrated in vacuo to give the product (62) (1.13 g) as acolorless oil. To this was added 3 mL of THF and the solution stored at−78° C. This was used in the next step without further purification.

Example 63 Synthesis of 2-methoxyethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (63)

Step 1: Synthesis of Sodium5-(2-methoxyethoxy)-2,2-dimethyl-5-oxopentanoate (63a)

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in2-methoxyethanol (30 mL) was added a solution sodium 2-methoxyethanolate(4.27 g, 43.5 mmol) in 2-methoxyethanol (30 mL). After 20 h of stirring,the solvent was evaporated and the resulting solid was suspended in Et₂O(80 mL). The mixture was filtered and the solid was washed with Et₂O(2×40 mL). The solid was dried under high vacuum to afford the product(63a) (6.44 g, 76%) as a solid. ¹H-NMR (300 MHz, D₂O): δ 4.30-4.27 (m,2H), 3.75-3.72 (m, 2H), 3.42 (s, 3H), 2.41-2.36 (m, 2H), 1.83-1.78 (m,2H), 1.12 (s, 6H). The spectrum revealed that the product wascontaminated with a small amount of an unidentified substance.

Step 2: Synthesis of 2-methoxyethyl 5-hydroxy-4,4-dimethylpentanoate(63b)

To a suspension of sodium5-(2-methoxyethoxy)-2,2-dimethyl-5-oxopentanoate (63a) (6.44 g, 26.8mmol) in a mixture of THF (58 mL) and DMF (19 mL) was added isopropylchloroformate, 1.0M in toluene (40.2 mL, 40.2 mmol) at 0° C. and stirredfor 10 min. After 4 h of stirring at room temperature, the mixture wasstored at −78° C. overnight. The suspension was cooled to 0° C. andsodium borohydride (1.81 g, 53.6 mmol) was added. The mixture wasstirred for 20 min and then MeOH (9.6 mL) was added to the solution(reaction monitored by TLC using 3:7 EtOAc/hexanes as eluent). After 30min of stirring, EtOAc (50 mL) with a few drops of Et₃N followed by asaturated aqueous solution of NH₄Cl (50 mL) were added. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×80 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give the product (63b) (2.54 g,46% crude).

Step 3: Synthesis of 2-methoxyethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (63)

A solution of sulfuryl chloride (0.36 mL, 4.9 mmol) in Et₂O (8 mL) wascooled to −78° C. under a nitrogen atmosphere. A solution of2-methoxyethyl 5-hydroxy-4,4-dimethylpentanoate (63b) (0.50 g, 2.4 mmol)and pyridine (0.40 mL, 4.9 mmol) in Et₂O (8 mL) was added dropwise tothe sulfuryl chloride solution over the course of 10 min. The syringewas rinsed with Et₂O (3×1 mL) and the rinse was also added to themixture. The mixture was stirred for 4.5 h (reaction monitored by TLCusing 2:8 EtOAc/hexanes as eluent). The solids were filtered-off and thefiltrate concentrated in vacuo to give the product (63) (0.60 g, 2.0mmol) as a colorless oil. To this was added 3 mL of THF and the solutionwas stored at −78° C. This was used in the next step without furtherpurification.

Example 64 Synthesis of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl Propionate (64)

Step 1: Synthesis of 5,5-dimethyltetrahydro-2H-pyran-2-one (64a)

To a solution of ethyl 5-hydroxy-4,4-dimethylpentanoate (57a) (26.5 g,152.1 mmol) in dichloromethane (683 mL) was added trifluoroacetic acid(1.75 mL, 22.8 mmol). The mixture was stirred at room temperature for 3d. The reaction was quenched with a saturated aqueous sodium bicarbonatesolution (150 mL), stirred rapidly for 30 min, and the layers wereseparated. The organic layer was washed with brine (150 mL), dried(Na₂SO₄), and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel flash using EtOAc/hexanes (0:1 to45:55) as eluent to give the product (64a) (8.79 g, 45%) as a colorlessoil. The product was used in the next step without further purificationand was contaminated with small amounts of unidentified byproducts.¹H-NMR (300 MHz, CDCl₃): δ 3.97 (s, 2H), 2.56 (t, J=7.4 Hz, 2H), 1.69(t, J=7.4 Hz, 2H), 1.05 (s, 6H).

Step 2: Synthesis of 3,3,5,5-tetramethyltetrahydro-2H-pyran-2-one (64b)

5,5-Dimethyltetrahydro-2H-pyran-2-one (64a) (8.79 g, 68.6 mmol) wasdissolved in anhydrous DMF (150 mL) and the resulting solution wascooled to 0° C. under an inert atmosphere of argon. Sodium hydride, 60%in mineral oil (8.23 g, 205.7 mmol) was added in one portion and themixture stirred for 20 min. This was followed by the drop-wise additionof MeI (17.1 mL, 274.3 mmol). The resulting solution was stirred at 0°C. for 20 min and then at room temperature for 3 d. The mixture wasdiluted with EtOAc (350 mL) and then quenched at 0° C. via the carefuldropwise addition of a saturated aqueous solution of NH₄Cl (100 mL). Theaqueous and organic layers were separated, and the aqueous layer wasextracted with EtOAc (350 mL). The combined organic layers were washedwith H₂O (6×300 mL), brine (300 mL), dried (Na₂SO₄), and concentratedunder vacuum. The residue was purified by column chromatography onsilica using EtOAc/hexanes (1:9) as eluent to give the product (64b)(3.42 g, 32%). The product was used in the next step without furtherpurification and was contaminated with small amounts of variousunidentified byproducts. ¹H-NMR (300 MHz, CDCl₃): δ 4.01 (s, 2H), 1.62(s, 2H), 1.30 (s, 6H), 1.02 (s, 6H).

Step 3: Synthesis of 2,2,4,4-tetramethylpentane-1,5-diol (64c)

A necked round bottom flask containing a stirring slurry of 95% LiAlH₄(0.87 g, 21.6 mmol) in Et₂O (126 mL) was cooled to 0° C. under anatmosphere of argon. To this slurry was added a solution of3,3,5,5-tetramethyltetrahydro-2H-pyran-2-one (64b) (2.94 g, 18.8 mmol)in Et₂O (50 mL) under an inert atmosphere of argon. This was warmed toroom temperature and stirred overnight. The mixture was cautiouslyquenched with H₂O (80 mL) then 3 M NaOH (120 mL) and stirred for 30 min.The mixture was filtered through a pad of Celite®, and the pad wasrinsed thoroughly with Et₂O. The aqueous and organic layers wereseparated, and the aqueous layer was extracted with Et₂O (3×100 mL). Thecombined organic layers were concentrated under vacuum and the residuewas purified by column chromatography on silica gel using EtOAc/hexanes(2:8 to 6:4) as eluent to give the product (64c) (2.59 g, 86%) as asolid. ¹H-NMR (300 MHz, CDCl₃): δ 3.41 (s, 4H), 2.55 (s, 2H), 1.34 (s,2H), 0.95 (s, 12H)

Step 4: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl Propionate(64d)

To a stirring solution of 2,2,4,4-tetramethylpentane-1,5-diol (64c)(0.48 g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL) wasadded propionyl chloride (0.26 mL, 3.0 mmol) dropwise over the course of30 min at ca. 0° C. (ice bath). The reaction mixture was stirredovernight at room temperature. The mixture was diluted with H₂O (20 mL),and the layers were separated. The aqueous layer was extracted with DCM(2×20 mL), and the combined organic layers were washed with brine (20mL), dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel EtOAc/hexanes (5:95 to6:4) as eluent to give the product (64d) (411 mg, 63%). ¹H-NMR (300 MHz,CDCl₃): δ 3.85 (s, 2H), 3.32 (s, 2H), 2.37 (q, J=7.7 Hz, 2H), 1.50 (s,1H), 1.36 (s, 2H), 1.16 (t, J=7.5 Hz, 3H), 1.03 (s, 6H), 0.99 (s 6H).

Step 5: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentylPropionate (64)

A solution of sulfuryl chloride (0.136 mL, 1.9 mmol) in Et₂O (6.4 mL)was cooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl propionate (39d) (404 mg, 1.9 mmol)and pyridine (0.15 mL, 1.9 mmol) in Et₂O (6.4 mL) was added dropwise tothe sulfuryl chloride solution over the course of 10 min. The mixturewas warmed to room temperature and stirred for 70 min. The solids werefiltered to give a solution of the product (64) in Et₂O as the filtrate.The yield was assumed quantitative, and the mixture was used in the nextstep without further purification.

Example 65 Synthesis of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl Benzoate (65)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl Benzoate (65a)

To a stirred solution of 2,2,4,4-tetramethylpentane-1,5-diol (64c) (0.48g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL) was addedbenzoyl chloride (0.37 mL, 3.0 mmol) dropwise over the course of 30 minat ca. 0° C. (ice bath) under an atmosphere of argon. The reactionmixture was stirred overnight at room temperature. The mixture wasdiluted with H₂O (20 mL), and the layers were separated. The aqueouslayer was extracted with DCM (2×20 mL), and the combined organic layerswere washed with brine (20 mL), dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (5:95 to 1:1) as eluent to give the product (65a)(548 mg, 69%) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 8.06 (d, J=8.4 Hz,2H), 7.59-7.55 (m, 1H), 7.48-7.43 (m, 2H), 4.09 (s, 2H), 3.35 (s, 2H),1.48 (s, 2H), 1.13 (s, 6H), 1.02 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentylBenzoate (65)

A solution of sulfuryl chloride (0.15 mL, 2.0 mmol) in Et₂O (8.5 mL) wascooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl benzoate (65a) (541 mg, 2.0 mmol)and pyridine (0.17 mL, 2.0 mmol) in Et₂O (8.5 mL) was added dropwise tothe sulfuryl chloride solution over the course of 10 min. The mixturewas stirred at 0° C. for 20 min, then at room temperature for 90 min.The mixture was filtered and the filtrate used to provide a solution ofthe product (65) in Et₂O (ca. 20 mL). The yield was assumed quantitativeand the product was used in the next step without further purification.

Example 66 Synthesis of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate(66)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl2,6-dimethylbenzoate (66a)

To a stirred solution of 2,2,4,4-tetramethylpentane-1,5-diol (61c) (0.48g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL) was added2,6-dimethylbenzoyl chloride (0.45 mL, 3.0 mmol) dropwise over thecourse of 30 min at 0° C. (ice bath) under an atmosphere of argon. Thereaction mixture was stirred overnight at room temperature. The mixturewas diluted with H₂O (20 mL), and the layers were separated. The aqueouslayer was extracted with DCM (2×20 mL), and the combined organic layerswere washed with brine (20 mL), dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (5:95 to 1:1) as eluent to give the product (66a)(462 mg, 53%) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 7.22-7.17 (m, 1H),7.04 (d, J=7.5 Hz, 2H), 4.10 (s, 2H), 3.32 (s, 2H), 2.33 (s, 6H), 1.41(s, 2H), 1.10 (s, 6H), 1.00 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethylbenzoate (66)

A solution of sulfuryl chloride (0.11 mL, 1.5 mmol) in Et₂O (7 mL) wascooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate (66a) (453 mg,1.5 mmol) and pyridine (0.13 mL, 1.5 mmol) in Et₂O (7 mL) was addeddropwise to the sulfuryl chloride solution over the course of 10 min.The mixture was stirred in an ice bath for 20 min, then at roomtemperature for 90 min. The mixture was filtered and the filtrate storedto give a solution of the product (66) in Et₂O (ca. 20 mL). The yieldassumed quantitative. This mixture was used in the next step withoutfurther purification (a small quantity was concentrated under vacuum andthe NMR taken of the residue). ¹H-NMR (300 MHz, CDCl₃): δ 7.21 (t, J=7.7Hz, 1H), 7.05 (d, J=7.2 Hz, 2H), 4.20 (s, 2H), 4.07 (s, 2H), 2.32 (s,6H), 1.50 (s, 2H), 1.14 (s, 6H), 1.12 (s, 6H).

Example 67 Synthesis of (3-methyl-2-oxotetrahydrofuran-3-yl)methylSulfochloridate (67)

Pyridine (0.28 mL, 3.5 mmol) was added to a stirred mixture of3-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (prepared according toSynlett 2010, 2625-2627) (0.30 g, 2.3 mmol) and Et₂O (8 mL) under anatmosphere of argon. The solution was cooled to −78° C. and sulfurylchloride (0.28 mL, 3.5 mmol) in Et₂O (3 mL) was slowly added at −78° C.The mixture was stirred at −78° C. for 1 h and then warmed to roomtemperature and stirred for 1 h. The reaction mixture was filtered toremove the pyridine salt, and the filtrate was concentrated under vacuumto give the product (67) as an oil, that was used directly in the nextstep without further purification (yield assumed quantitative).

Example 68 Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropylPivalate (68)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl Pivalate (68a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (5.07 g, 48.7mmol) in DCM (50 mL) at 0° C. under an atmosphere of argon was addedtrimethylacetyl chloride (2.0 mL, 16.2 mmol), pyridine (2.63 mL, 32.5mmol) and N,N-4-dimethylaminopyridine (0.4 g, 3.2 mmol). The mixture wasallowed to warm to room temperature and stirred at room temperatureovernight. The mixture was cooled to 0° C. and the reaction was quenchedwith the addition of 1N HCl (50 mL), then extracted with DCM (twice).The combined organic layers were washed with sat. sodium bicarbonate andbrine, then dried (Na₂SO₄), and concentrated under vacuum. The residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 1:5) as eluent to give the product (68a) as an oil. ¹H-NMR (300MHz, CDCl₃): δ 3.92 (s, 2H), 3.27 (s, 2H), 1.22 (s, 9H), 0.92 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl Pivalate(68)

Pyridine (0.75 mL, 9.3 mmol) was added to a stirred mixture of3-hydroxy-2,2-dimethylpropyl pivalate (68a) (1.17 g, 6.2 mmol) and Et₂O(20 mL) under an atmosphere of argon. The solution was cooled to −78° C.and sulfuryl chloride (0.75 mL, 9.3 mmol) in Et₂O (8 mL) was slowlyadded at −78° C. The mixture was stirred at −78° C. for 1 h and thenwarmed to room temperature, and stirred for 1 h. The reaction mixturewas filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (68) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative).

Example 69 Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl3-chloro-2,6-dimethoxybenzoate (69)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethoxybenzoate(69a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (3.89 g, 37.4mmol) in DCM (40 mL) at 0° C. under an atmosphere of argon was added2,6-dimethoxybenzoyl chloride (80% purity; 3.13 g, 12.5 mmol), pyridine(2.02 mL, 24.9 mmol), and N,N-4-dimethylaminopyridine (0.3 g, 2.5 mmol).The mixture was allowed to warm to room temperature and stirred at roomtemperature overnight. The mixture was cooled to 0° C. and the reactionwas quenched by the addition of 1N HCl (50 mL), then extracted with DCM(twice). The combined organic layers were washed with sat. sodiumbicarbonate and brine, then dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 1:5) as eluent to give the product (69a) asan oil. ¹H-NMR (300 MHz, CDCl₃): δ 7.19 (t, J=5.0 Hz, 1H), 6.48 (d,J=8.1 Hz, 2H), 4.09 (s, 2H), 3.71 (s, 6H), 3.33 (s, 2H), 0.89 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl3-chloro-2,6-dimethoxybenzoate (69)

Pyridine (0.16 mL, 2.0 mmol) was added to a stirred mixture of3-hydroxy-2,2-dimethylpropyl 2,6-dimethoxybenzoate (69a) (0.35 g, 1.3mmol) and Et₂O (10 mL) under an atmosphere of argon. The solution wascooled to −78° C. and sulfuryl chloride (0.16 mL, 2.0 mmol) in Et₂O (8mL) was slowly added at −78° C. The mixture was stirred at −78° C. for 1h and then warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (69) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative). ¹H-NMR (300 MHz, CDCl₃): δ 7.36 (d, J=8.7 Hz,1H), 6.66 (d, J=8.7 Hz, 1H), 4.35 (s, 2H), 4.21 (s, 2H), 3.89 (s, 3H),3.81 (s, 3H), 1.13 (s, 6H).

Example 70 Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl2,6-dimethylbenzoate (70)

Step 1: Synthesis of 2,2,3,3-tetramethylbutane-1,4-diol (70a)

A solution of 3,3,4,4-tetramethyldihydrofuran-2(3H)-one (preparedaccording to U.S. Pat. No. 3,658,849) (1.0 g, 7.0 mmol) in Et₂O (28 mL)was added to a stirring slurry of LiAlH₄ (95%; 0.32 g, 8.1 mmol) in Et₂O(28 mL) at 0° C. under an atmosphere of argon. The mixture was warmed toroom temperature and stirred overnight. Sodium sulfate decahydrate wasslowly added until effervescence in the flask ceased. The solid wasfiltered through a pad of Celite R, and the pad was washed with EtOAc.The filtrate was concentrated under vacuum, and the residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 7:3)as eluent to give the product (70a) (0.7 g) as a solid. ¹H-NMR (300 MHz,CDCl₃): δ 3.41 (s, 4H), 0.88 (s, 12H).

Step 2: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl2,6-dimethylbenzoate (70b)

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (70a) (0.71g, 4.9 mmol) in DCM (15 mL) at 0° C. under an atmosphere of argon wasadded 2,6-dimethylbenzoyl chloride (0.2 mL, 1.6 mmol), pyridine (0.26mL, 3.2 mmol) and N,N-4-dimethylaminopyridine (0.04 g, 0.3 mmol). Themixture was allowed to warm to room temperature and stirred at roomtemperature overnight. The mixture was cooled to 0° C. and the reactionwas quenched by the addition of 1N HCl (15 mL), then extracted with DCM(twice). The combined organic layers were washed with sat. sodiumbicarbonate and brine, then dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 3:2) as eluent to give the product (70b) asan oil (266 mg). ¹H-NMR (300 MHz, CDCl₃): δ 7.18 (t, J=8.4 Hz, 1H), 7.02(d, J=6.9 Hz, 2H), 4.25 (s, 2H), 3.51 (s, 2H), 2.31 (s, 6H), 0.98 (s,6H), 0.93 (s, 6H).

Step 3: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl2,6-dimethylbenzoate (70)

Pyridine (0.11 mL, 1.3 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl 2,6-dimethylbenzoate (70b) (0.26 g,0.9 mmol) and Et₂O (10 mL) under an atmosphere of argon. The solutionwas cooled to −78° C. and sulfuryl chloride (0.11 mL, 1.3 mmol) in Et₂O(3 mL) was slowly added at −78° C. The mixture was stirred at −78° C.for 1 h and then warmed to room temperature and stirred for 1 h. Thereaction mixture was filtered to remove the pyridine salt, and thefiltrate was concentrated under vacuum to give the product (70) as anoil, that was used directly in the next step without furtherpurification (yield assumed quantitative).

Example 71 Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutylBenzoate (71)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl Benzoate (71a)

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (67a) (0.74g, 5.0 mmol) in DCM (15 mL) at 0° C. under an atmosphere of argon wasadded benzoyl chloride (0.25 mL, 2.0 mmol), pyridine (0.33 mL, 4.0 mmol)and N,N-4-dimethylaminopyridine (0.05 g, 0.4 mmol). The mixture wasallowed to warm to room temperature and stirred at room temperatureovernight. The mixture was cooled to 0° C. and the reaction was quenchedby the addition of 1N HCl (15 mL), then extracted with DCM (twice). Thecombined organic layers were washed with sat. sodium bicarbonate andbrine, then dried (Na₂SO₄), and concentrated under vacuum. The residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 3:2) as eluent to give the product (71a) as an oil. ¹H-NMR (300MHz, CDCl₃): δ 8.05 (d, J=7.2 Hz, 2H), 7.58 (t, J=7.4 Hz, 1H), 7.46 (t,J=7.4 Hz, 2H), 4.27 (s, 2H), 3.59 (s, 2H), 1.05 (s, 6H), 0.99 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutylBenzoate (71)

Pyridine (0.29 mL, 3.6 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl benzoate (71a) (0.70 g, 2.8 mmol) andEt₂O (10 mL) under an atmosphere of argon. The solution was cooled to−78° C. and sulfuryl chloride (0.29 mL, 3.6 mmol) in Et₂O (3 mL) wasslowly added at −78° C. The mixture was stirred at −78° C. for 1 h andthen warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (71) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative).

Example 72 Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutylPropionate (72)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl Propionate (72a)

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (70a) (0.59g, 4.0 mmol) in DCM (15 mL) at 0° C. under an atmosphere of argon wasadded propionyl chloride (0.25 mL, 3.1 mmol), pyridine (0.33 mL, 4.0mmol) and N,N-4-dimethylaminopyridine (0.05 g, 0.4 mmol). The mixturewas allowed to warm to room temperature and stirred at room temperatureovernight. The mixture was cooled to 0° C. and the reaction was quenchedby the addition of 1N HCl (15 mL), and then extracted with DCM (twice).The combined organic layers were washed with sat. sodium bicarbonate andbrine, then dried (Na₂SO₄), and concentrated under vacuum. The residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 3:2) as eluent to give di-acylated material, followed by theproduct (72a) (300 mg) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 3.99 (s,2H), 3.49 (s, 2H), 2.38-2.31 (q, 2H), 1.15 (t, J=7.8 Hz, 3H), 0.91 (d,J=4.8 Hz, 12H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutylPropionate (72)

Pyridine (0.16 mL, 1.9 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl propionate (72a) (0.30 g, 1.5 mmol)and Et₂O (10 mL) under an atmosphere of argon. The solution was cooledto −78° C. and sulfuryl chloride (0.16 mL, 1.9 mmol) in Et₂O (3 mL) wasslowly added at −78° C. The mixture was stirred at −78° C. for 1 h andthen warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (72) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative).

Example 73 Synthesis of (3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methylSulfochloridate (73)

Step 1: Synthesis of3-((benzyloxy)methyl)-3-methyltetrahydro-2H-pyran-2-one (73a)

δ-Valerolactone (5.23 g, 52.2 mmol) was dissolved in a mixture of THF(120 mL) and HMPA (9.2 mL) under an atmosphere of argon. The reactionmixture was cooled to −78° C. and stirred for 10 min. A solution oflithium diisopropylamide, 2.0 M in THF (28.7 mL, 57.5 mmol) was addeddropwise over 5 min. The reaction was stirred at −78° C. for 30 min andthen neat MeI (3.3 mL, 52.8 mmol) was added to the reaction over 5 min.The mixture was stirred at −78° C. for 30 min then removed from thecooling bath and allowed to warm to 0° C. and stirred for 30 min (note:the mixture gradually became yellow during this time). The mixture wasre-cooled to −78° C. and stirred for 10 min, and then an additionalamount of lithium diisopropylamide, 2.0 M in THF (28.7 mL, 57.5 mmol)was added over 5 min. The reaction was stirred at −78° C. for 30 min,then neat benzyl chloromethyl ether (70%; 10.5 mL, 52.8 mmol) was addedover 5 min. The mixture was left to warm to room temperature and stirredfor 16h. The solvent was then removed under vacuum and the residue waspartitioned between saturated ammonium chloride (200 mL) and EtOAc (200mL). The aqueous layer was extracted with EtOAc (2×100 mL) and thecombined organic layers were washed with brine (2×100 mL), dried(Na₂SO₄), filtered, and concentrated under vacuum (19 g). The residuewas dry-loaded onto silica gel and purified by column chromatography onsilica gel (120 g cartridge) using EtOAc/hexanes as eluent to give theproduct contaminated with an impurity (6.9 g). The residue wasre-purified by column chromatography on silica gel using DCM/hexanes(0:1 to 4:1) as eluent to give the product (73a) (1.76 g) as a liquid.¹H-NMR (300 MHz, CDCl₃): δ 7.29-7.37 (m, 5H), 4.61 (dd, J=21.0, 12.3 Hz,2H), 4.32-4.38 (m, 2H), 3.26-3.81 (dd, J=15.8, 8.1 Hz, 2H), 2.21-2.30(m, 1H), 1.87-1.94 (m, 2H), 1.59-1.66 (m, 1H), 1.23 (s, 3H).

Step 2: Synthesis of 3-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2-one(73b)

3-((Benzyloxy)methyl)-3-methyltetrahydro-2H-pyran-2-one (73a) (0.52 g,2.2 mmol) was dissolved in 2-propanol (25 mL) and the solution wasdegassed and back-flushed with argon. (Note: do not use MeOH as solvent,as it may ring-open the lactone during hydrogenation). Palladium oncarbon, 10% (0.26 g, 0.2 mmol), was added to the mixture and the systemwas sealed. The reaction was degassed and back-flushed with hydrogen (3times) and stirred under an atmosphere of hydrogen for 2 h. Thesuspension was filtered through a pad of Celite R, and the filter cakewashed with fresh 2-propanol (2×50 mL). The filtrate was concentratedunder vacuum, and the product (73b) was used without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 4.27-4.45 (m, 2H), 3.67 (d,J=11.4 Hz, 1H), 3.52 (d, J=11.1 Hz, 1H), 1.84-2.03 (m, 2H), 1.58-1.64(m, 1H), 1.29 (s, 3H).

Step 3: Synthesis of (3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methylSulfochloridate (73)

A solution of 3-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2-one (73b)(0.32 g, 2.2 mmol) and pyridine (0.21 mL, 2.6 mmol) in Et₂O (10 mL) wascooled to −78° C. under an atmosphere of argon. Neat sulfuryl chloride(0.21 mL, 2.6 mmol) was added dropwise to the above solution via asyringe. The mixture was stirred at −78° C. for 10 min, then the flaskwas warmed to room temperature and stirred for 1 h (monitored by TLCEtOAc/hexanes, 3:7). A precipitate formed to give a thick suspension.The suspension was filtered through a 0.45 μM Teflon® filter, and thefilter cake rinsed with fresh Et₂O (2×5 mL). An aliquot (0.5 mL) wastaken and concentrated, and an NMR was obtained for the mixture. Theremaining solution containing the product (73) was used directly in thenext step. ¹H-NMR (300 MHz, CDCl₃): δ 4.87 (d, J=9.3 Hz, 1H), 4.25-4.50(m, 2H), 4.32 (d, J=8.7 Hz, 1H), 2.00-2.20 (m, 2H), 1.75-2.00 (m, 2H),1.39 (s, 3H).

Example 74 Synthesis of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl Acetate (74)

Step 1: Synthesis of ethyl 3-(2-methoxyphenyl)-2,2-dimethylpropanoate(74a)

A stirred solution of lithium diisopropylamide, 2.0 M in THF (26.6 mL,53.2 mmol) was diluted with THF (100 mL) was cooled to −78° C. under anatmosphere of argon, and stirred for 5 min. Neat ethyl isobutyrate (6.68mL, 49.7 mmol) was added dropwise over 15 min, and the mixture allowedto stir at −78° C. for 1h. A solution of1-(bromomethyl)-2-methoxybenzene (prepared according to J. Am. Chem.Soc. 2013, 135, 11951) (12.0 g, 59.7 mmol) in THF (100 mL) was addeddropwise over 30 min. The mixture was allowed to warm to roomtemperature and stirred for 20 h. The reaction was quenched with brine(100 mL) and extracted with Et₂O (4×100 mL). The combined organic layerswere dried (MgSO₄), filtered, and concentrated under vacuum. The cruderesidue was purified by column chromatography on silica gel (120 gcolumn) using EtOAc/hexanes (0:1 to 5:95) as eluent to give the product(74a) as a liquid (8.06 g, 68%). ¹H-NMR (300 MHz, CDCl₃): δ 7.18 (dt,J=1.8, 8.1 Hz, 1H), 7.06 (dd, J=1.5, 8.1 Hz, 1H), 6.82-6.87 (m, 2H),4.12 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 2.92 (s, 2H), 1.26 (t, J=6.9 Hz,3H), 1.15 (s, 6H).

Step 2: Synthesis of 3,3-dimethylchroman-2-one (74b)

Ethyl 3-(2-methoxyphenyl)-2,2-dimethylpropanoate (74a) (8.1 g, 34.2mmol) was dissolved in DCM (200 mL) and cooled to 0° C. under anatmosphere of argon. A solution of BBr₃ (3.6 mL, 37.7 mmol) in DCM (100mL) was added dropwise to the cold solution. The mixture was warmed toroom temperature and stirred overnight (a solid formed during thereaction). The colored suspension was cooled in an ice water bath andwater (150 mL) was added to the mixture. The organic and aqueous layerswere separated, and the aqueous layer was extracted with DCM (3×75 mL).The combined organic layers were dried (MgSO₄; note: the solution becamedarker), filtered, and concentrated under vacuum to give the product(74b) (4.85 g, 80%) as an oil. This material was used without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 7.01-7.25 (m, 3H), 2.85 (s,2H), 1.29 (s, 6H).

Step 3: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenol (74c)

LiAlH₄ (1.94 g, 51.1 mmol) was suspended in Et₂O (52.5 mL) under anatmosphere of argon and the mixture was cooled to 0° C. in an ice waterbath. A solution of 3,3-dimethylchroman-2-one (74b) (4.85 g, 27.5 mmol)in Et₂O (50 mL) and added dropwise to the suspension over 30 min. Themixture was warmed to room temperature and stirred for 20 h. The mixturewas cooled in an ice water bath and water (2 mL), 15% aqueous sodiumhydroxide (2 mL), and water (6 mL), were sequentially added by slowaddition. The mixture was warmed to room temperature and stirred for 15min. Anhydrous MgSO₄ was added to the suspension and the mixture stirredfor 15 min. The mixture was filtered, and the filter cake washed withEt₂O (3×50 mL). The filtrate was concentrated under vacuum to give theproduct (74c) (4.34 g, 88%) as a solid. This material was used withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃): δ 7.15 (dt, J=8.1, 1.5Hz, 1H), 7.04 (dd, J=7.5, 1.8 Hz, 1H), 6.82-7.01 (m, 2H), 3.22 (s, 2H),2.61 (s, 2H), 0.98 (s, 6H).

Step 4: Synthesis of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (74d)

A solution of 2-(3-hydroxy-2,2-dimethylpropyl)phenol (74c) (4.0 g, 22.2mmol) and imidazole (3.8 g, 56.0 mmol) was dissolved in DMF (50 mL) andtert-butyldimethylsilyl chloride (4.0 g, 26.6 mmol) was added to thesolution and stirred for 2 h. The solvent was removed under high vacuumand the residue was purified by column chromatography on silica gel (40g cartridge) with hexanes (5:95 to 2:3) as eluent to give the product(74d) as an oil (7.34 g, >100%). The compound was approximately 90% pureand was used directly in the next step without further purification.¹H-NMR (300 MHz, CDCl₃): δ 7.11 (dt, J=7.5, 1.8 Hz, 1H), 7.10 (dd,J=7.5, 1.8 Hz, 1H), 6.90 (dd, J=8.1, 1.5 Hz, 1H), 6.79 (dt, J=6.9, 0.9Hz, 1H), 3.17 (s, 2H), 2.57 (s, 2H), 0.97 (s, 9H), 0.92 (s, 6H), 0.13(s, 6H).

Step 5: Synthesis of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl Acetate(74e)

A solution of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (74d) (ca.90% purity; 2.5 g, 7.6 mmol) and Et₃N (2.3 g, 22.9 mmol) in THF (90 mL)was cooled to 0° C. in an ice bath under an atmosphere of argon. Acetylchloride (0.65 mL, 9.2 mmol) was added dropwise to the mixture, andafter complete addition the ice bath was removed. The reaction wasallowed to warm to room temperature and stirred for 2 h. The suspensionwas filtered and the solid washed with fresh THF (2×20 mL). The filtratewas concentrated under vacuum and the residue dry-loaded onto silicagel, then purified by column chromatography on silica gel (40 gcartridge) using 0-8% EtOAc/hexanes (0:1 to 8:92) as eluent to give theproduct (74e) (2.16 g, 84%) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ7.11-7.27 (m, 3H), 7.04 (d, J=7.5 Hz, 1H), 3.25 (s, 2H), 2.51 (s, 2H),2.30 (s, 3H), 0.93 (s, 9H), 0.81 (s, 6H), 0.06 (s, 6H).

Step 6: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenyl Acetate and3-(2-hydroxyphenyl)-2,2-dimethylpropyl Acetate (74f)

Pyridine hydrofluoride (70%, 1.3 mL, 10.4 mmol) was added to a stirredsolution of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl acetate(74e) (0.70 g, 2.1 mmol) and pyridine (2.5 mL, 31.2 mmol) in THF (25 mL)at room temperature under an atmosphere of argon, and the mixture wasstirred for 24 h. The solvent was removed under vacuum (bath temperatureset to 25° C.), and the residue was dissolved in EtOAc (100 mL), washedwith brine (3×75 mL), dried (Na₂SO₄), filtered, and concentrated undervacuum to give a mixture of the desired alcohol and3-(2-hydroxyphenyl)-2,2-dimethylpropyl acetate in a 65:35. NMR analysisshowed the presence of both esters of the product (74f). This materialwas used directly in the next step without further purification. ¹H-NMR(300 MHz, CDCl₃) of desired product: δ 6.8-7.26 (m, 4H), 3.79 (s, 2H),3.27 (s, 2H), 2.62 (s, 2H), 2.53 (s, 2H), 2.33 (s, 3H), 2.13 (s, 3H),0.974 (s, 6H), 0.90 (s, 6H).

Step 7: Synthesis of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl Acetate (74)

A solution of sulfuryl chloride (172 μL, 2.1 mmol) in Et₂O (6.8 mL) wascooled to −78° C. under an atmosphere of argon. A solution of2-(3-hydroxy-2,2-dimethylpropyl)phenyl acetate (74f) (0.43 g, 1.9 mmol)and pyridine (172 μL, 2.1 mmol) in Et₂O (2.0 mL) was added dropwise tothe sulfuryl chloride solution via cannula. The mixture was stirred at−78° C. for 10 min, then the flask was warmed to room temperature andstirred for 1.5 h (monitored by TLC 30% EtOAc/hexanes). The suspensionwas filtered through a 0.45 μm PTFE syringe filter, and the syringefilter was rinsed with fresh Et₂O (10 mL) to provide the product (74).The filtrate was used immediately in the next step without furtherpurification. The yield was assumed to be quantitative.

Example 75 Synthesis of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl Pivalate (75)

Step 1: Synthesis of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl Pivalate(75a)

2-(3-((tert-Butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (0.9 g,3.1 mmol) and N,N-4-dimethylaminopyridine (0.93 g, 7.6 mmol) weredissolved in THF (50 mL) under an atmosphere of argon. Trimethylacetylchloride (0.45 mL, 3.7 mmol) was added dropwise to the mixture at roomtemperature to immediately form a white solid, and the addition wascontinued until a suspension was formed. The reaction was stirred atroom temperature for 2 h, and then filtered and the filter cake washedwith THF (10 mL). The filtrate was dry-loaded on to silica gel (15 g)and purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 6:94) as eluent to give the product (75a) contaminated with ca.3% of starting material by NMR analysis. This material was used withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃): δ 7.27 (dd, J=7.2, 2.1Hz, 1H), 7.21 (dt, J=7.5, 1.8 Hz, 1H), 7.15 (dt, J=7.8, 1.8 Hz, 1H),6.97 (dd, J=8.1, 1.8 Hz, 1H), 3.25 (s, 2H), 2.49 (s, 2H), 1.38 (s, 9H),0.92 (s, 9H), 0.82 (s, 6H), 0.05 (s 6H).

Step 2: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenyl Pivalate(75b)

Pyridine hydrofluoride (70%, 1.3 mL, 10.4 mmol) was added to a stirredsolution of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl pivalate(75a) (0.70 g, 1.8 mmol) and pyridine (2.5 mL, 31.2 mmol) in THF (25 mL)at room temperature under an atmosphere of argon, and the mixture wasstirred for 24 h. The solvent was removed under vacuum (bath temperatureset to 25° C.), and the residue was dissolved in EtOAc (100 mL) andwashed with brine (3×75 mL), dried (Na₂SO₄), filtered, and concentratedunder vacuum to give the desired product (75b) as an oil. This materialwas used directly in the next step without further purification. ¹H-NMR(300 MHz, CDCl₃): δ 7.12-7.26 (m, 3H), 6.98 (m, 1H), 3.31 (s, 2H), 2.51(s, 2H), 1.39 (s, 9H), 0.89 (s, 9H).

Step 3: Synthesis of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl Pivalate (75)

A solution of sulfuryl chloride (173 μL, 2.1 mmol) in Et₂O (7.5 mL) wascooled to −78° C. under an argon atmosphere. A solution of2-(3-hydroxy-2,2-dimethylpropyl)phenyl pivalate (75b) (0.47 g, 1.8 mmol)and pyridine (173 μL, 2.1 mmol) in Et₂O (2.2 mL) was added dropwise tothe sulfuryl chloride solution via cannula. The mixture was stirred at−78° C. for 10 min, and then the flask was warmed to room temperatureand stirred for 1.5 h (monitored by TLC 30% EtOAc/hexanes). Thesuspension was filtered through a 0.45-μm PTFE syringe filter, and thesyringe filter was rinsed with fresh Et₂O to provide the product (75).The filtrate was used immediately in the next step without furtherpurification. The yield was assumed to be quantitative.

Example 76 Synthesis of S-(4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl)ethanethioate (73)

A solution of freshly distilled sulfuryl chloride (271 μL, 3.7 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of S-(4-hydroxy-3,3-dimethylbutyl) ethanethioate (preparedaccording to Chem. Commun. 2011, 47, 2038) (500 mg, 2.8 mmol) andpyridine (267 μL, 3.3 mmol) in Et₂O (3 mL) was added dropwise to thesulfuryl chloride solution over the course of 5 min. The flask wasrinsed with diethyl ether (2×5 mL) and the rinse was also added to thereaction mixture. The mixture was stirred at −78° C. for 1 h and allowedto warm to room temperature and stirred at room temperature for another20 min. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (12 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (76) as an oil which wasused immediately for the next step without further purification.

Example 77 Synthesis of S-(5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl)ethanethioate (77)

Step 1: Synthesis of 5-bromo-2,2-dimethylpentan-1-ol (74a)

DCM (18 mL) was added to LiBH₄ (0.66 g, 30.4 mmol) followed by dropwiseaddition of anhydrous MeOH (1.2 ml, 30.4 mmol) over 20 min under anatmosphere of argon. After the H₂ effervescence had ceased, a solutionof ethyl 5-bromo-2,2-dimethylpentanoate (prepared according to PCTApplication Publication No. 2011046771) (4.5 g, 19.0 mmol) in DCM (10mL) was added dropwise over 20 min. The reaction mixture was heated toreflux for 16 h, cooled to room temperature, and carefully hydrolyzedwith a saturated NH₄Cl solution (30 mL). The suspension was extractedwith DCM (3×50 mL). The combined organic layers were washed with 1N HCl(26 mL) and brine (40 mL), dried, and concentrated under vacuum to givethe product (77a) (3.61 g, 97%) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ3.39 (t, J=6.9 Hz, 2H), 3.24 (s, 2H), 1.90-1.76 (m, 2H), 1.48 (br. s,1H), 1.41-1.36 (m, 2H), 0.88 (s, 6H).

Step 2: Synthesis of S-(5-hydroxy-4,4-dimethylpentyl) ethanethioate(77b)

A solution of 5-bromo-2,2-dimethylpentan-1-ol (77a) (2.0 g, 10.3 mmol)and potassium thioacetate (2.34 g, 20.5 mmol) in acetone (22 mL) wasstirred under an inert atmosphere at room temperature for 23 h. Afterremoving the solvents under vacuum at room temperature, the residue waspurified by column chromatography on silica gel column usingEtOAc/hexanes (0:1 to 2:3) as eluent to give the product (77b) (1.2 g,61%) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 3.31 (s, 2H), 2.85 (t, J=7.8Hz, 2H), 2.32 (s, 3H), 1.62-1.48 (m, 2H), 1.32-1.21 (m, 2H), 0.86 (s,6H).

Step 3: Synthesis of S-(5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl)ethanethioate (77)

A solution of freshly distilled sulfuryl chloride (379 μL, 5.2 mmol) inEt₂O (8 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of S-(5-hydroxy-4,4-dimethylpentyl) ethanethioate (77b) (700mg, 3.6 mmol) and pyridine (374 μL, 4.6 mmol) in Et₂O (4 mL) was addeddropwise to the sulfuryl chloride solution over the course of 5 min. Themixture was stirred at −78° C. for 1 h, and then allowed to warm to roomtemperature. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (10 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (77) as an oil which wasused immediately for the next step without further purification.

Example 78 Synthesis of S-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (78) Step 1: Synthesis of S-(3-hydroxy-2,2-dimethylpropyl)ethanethioate (78a)

Potassium thioacetate (4.1 g, 35.8 mmol) was dissolved in DMF (20 mL)under an atmosphere of argon. 3-Hydroxy-2,2-dimethylpropyl4-methylbenzenesulfonate (prepared according to PCT ApplicationPublication No. 2012165648) (4.2 g, 16.3 mmol) was added, and themixture was stirred at 80° C. for 2.5 h. After cooling, brine (100 mL)was added, and the mixture was extracted with Et₂O (3×100 mL). Thecombined organic layers were washed with brine (5×50 mL), dried(Na₂SO₄), filtered, and concentrated under vacuum (residual DMF wasremoved by high vacuum). The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 15:85) aseluent to provide the product (78a) (1.06 g, 40%) as an oil. ¹H-NMR (300MHz, CDCl₃): δ 3.23 (br. s, 2H), 2.89 (s, 2H), 2.62 (br. s, 1H), 2.37(s, 3H), 0.94 (s, 6H).

Step 2: Synthesis of S-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (78)

A solution of freshly distilled sulfuryl chloride (283 μL, 3.9 mmol) inEt₂O (4 mL) was cooled to −78° C. under an argon atmosphere. A solutionof S-(3-hydroxy-2,2-dimethylpropyl) ethanethioate (78a) (520 mg, 3.1mmol) and pyridine (327 μL, 4.0 mmol) in Et₂O (6 mL) was added dropwiseto the sulfuryl chloride solution over the course of 5 min. The mixturewas stirred at −78° C. for 1 h, then allowed to warm to roomtemperature. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (10 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (78) as an oil which wasused immediately for the next step without further purification.

Example 79 Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl2,6-dimethylbenzoate (79)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethylbenzoate(79a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (2.5 g, 24.3 mmol)in DCM (60 mL) at ca. 0° C. (ice bath) under an atmosphere of argon, wasadded 2,6-dimethylbenzoyl chloride (1.2 mL, 8.1 mmol), pyridine (1.1 mL,13.7 mmol), and N,N-4-dimethylaminopyridine (99 mg, 0.8 mmol). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The reaction was quenched by theaddition of 1N HCl, and the mixture was extracted with DCM (twice). Thecombined organic extracts were washed with a saturated aqueous solutionof NaHCO₃ and brine, dried (MgSO₄), filtered and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (1:9 to 2:3) as eluent to give the product (79a)(1.5 g, 78%) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 7.21 (m, 1H), 7.04(m, 2H), 4.18 (s, 2H), 3.41 (s, 2H), 2.32 (s, 6H), 2.20 (br. s, 1H),0.99 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl2,6-dimethylbenzoate (79)

A solution of freshly distilled sulfuryl chloride (0.25 mL, 3.9 mmol) inEt₂O (6 mL) was cooled to −78° C. under an argon atmosphere. A solutionof 3-hydroxy-2,2-dimethylpropyl 2,6-dimethylbenzoate (79a) (500 mg, 2.1mmol) and pyridine (0.26 mL, 3.3 mmol) in Et₂O (6 mL) was added dropwiseto the sulfuryl chloride solution over the course of 5 min. The mixturewas stirred at −78° C. for 1 h, and then allowed to warm to roomtemperature. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (12 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (79) as an oil, which wasused immediately in the next step without further purification.

Example 80 Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl(3r,5r,7r)-adamantane-1-carboxylate (80)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl(3r,5r,7r)-adamantane-1-carboxylate (80a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (2.5 g, 24.3 mmol)in DCM (60 mL) at ca. 0° C. (ice bath) under an argon atmosphere, wasadded 1-adamantane-carbonyl chloride (1.36 g, 6.9 mmol), pyridine (1.1mL, 13.7 mmol), and N,N-4-dimethylaminopyridine (99 mg, 0.8 mmol). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The reaction was quenched by theaddition of 1N HCl, and the mixture was extracted with DCM (twice). Thecombined organic extracts were washed with a saturated aqueous solutionof NaHCO₃ and brine, dried (MgSO₄), filtered, and concentrated undervacuum to give the product (80a) (1.82 g, 100%) as an oil. ¹H-NMR (300MHz, CDCl₃): δ 3.91 (s, 2H), 3.25 (s, 2H), 2.01 (br. s, 3H), 1.89 (br.s, 6H), 1.71 (br. s, 7H), 0.91 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl(3r,5r,7r)-adamantane-1-carboxylate (80)

A solution of freshly distilled sulfuryl chloride (266 μL, 3.3 mmol) inEt₂O (4 mL) was cooled to −78° C. under an argon atmosphere. A solutionof 3-hydroxy-2,2-dimethylpropyl-adamantane-1-carboxylate (80a) (600 mg,2.2 mmol) and pyridine (0.28 mL, 3.5 mmol) in Et₂O (4 mL) was addeddropwise to the sulfuryl chloride solution over the course of 5 min. Theflask was rinsed with Et₂O (5 mL), and the rinse was also added to thereaction mixture. The mixture was stirred at −78° C. for 1 h, and thenallowed to warm to room temperature. The precipitate was filtered(quickly) and the filter cake rinsed with Et₂O (12 mL). The filtrate wasconcentrated under vacuum at room temperature to afford the titlecompound (80) as an oil, which was used immediately in the next stepwithout further purification.

Example 81 Synthesis of diethyl2-(((chlorosulfonyl)oxy)methyl)-2-methylmalonate (81)

Step 1: Synthesis of Diethyl 2-(hydroxymethyl)-2-methylmalonate (81a)

To a suspension of paraformaldehyde (1.3 g, 43.3 mmol) and K₂CO₃ (11 g,79 mmol) in EtOH (150 mL) was added diethyl 2-methylmalonate (4.5 mL,26.3 mmol). The mixture was stirred at room temperature for 17 h, thenfiltered through a pad of Celite®, and the filter cake washed with EtOH(2×30 mL). The filtrate was concentrated under vacuum and the residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 3:2) as eluent to afford the product (81a) (4.0 g, 74%) as anoil. ¹H-NMR (300 MHz, CDCl₃): δ 4.22 (q, J=6.9 Hz, 4H), 3.83 (d, J=6.9Hz, 2H), 2.90 (t, J=7.8 Hz, 1H), 1.42 (s, 3H), 1.26 (t, J=6.9 Hz, 6H).

Step 2: Synthesis of diethyl2-(((chlorosulfonyl)oxy)methyl)-2-methylmalonate (81)

A solution of freshly distilled sulfuryl chloride (248 μL, 3.0 mmol) inEt₂O (8 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of diethyl 2-(hydroxymethyl)-2-methylmalonate (81a) (500 mg,2.4 mmol) and pyridine (0.26 mL, 3.2 mmol) in Et₂O (4 mL) was addeddropwise to the sulfuryl chloride solution over the course of 5 min. Theflask was rinsed with Et₂O (5 mL), and the rinse was also added to thereaction mixture. The mixture was stirred at −78° C. for 1 h, and thenallowed to warm to room temperature. The precipitate was filtered(quickly) and the filter cake rinsed with Et₂O (12 mL). The filtrate wasconcentrated under vacuum at room temperature to afford the titlecompound (81) as an oil which was used immediately in the next stepwithout further purification.

Example 82 Synthesis of Propyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (82)

Step 1: Synthesis of Propyl 3-hydroxy-2,2-dimethylpropanoate (82a)

A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) wascharged and 1-propanol (15 mL) and conc. H₂SO₄ (70 μL, 1.3 mmol) in a 20mL-microwave vial was stirred at room temperature and then heated in amicrowave at 80° C. for 2 h and stirred at room temperature overnight.When the desired product was identified by TLC (EtOAc/hexanes; 3:7) themixture was concentrated under vacuum (40° C.) and diluted with EtOAc(80 mL) and H₂O (30 mL). The organic layer was washed with H₂O (twice),and brine, then dried (Na₂SO₄), filtered, and concentrated to give theproduct (82a) (1.18 g, 76%) as an oil. The material was used next stepdirectly without purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.07 (t, J=6.6Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1.70-1.61 (m, 2H), 1.19 (s,6H), 0.95 (t, J=7.5 Hz, 3H).

Step 2: Synthesis of Propyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (82)

A solution of freshly distilled sulfuryl chloride (194 μL, 2.7 mmol) inEt₂O (1.0 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of propyl 3-hydroxy-2,2-dimethylpropanoate (82a) (0.42 g, 2.6mmol) and pyridine (215 μL, 2.7 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 5 min. The flask wasrinsed with Et₂O (3×1 mL), and the rinse was added to the reactionmixture. The mixture was stirred at −78° C. for 5 min and then allowedto warm to room temperature and stirred for 1 h. The mixture wasfiltered and the filtrate was concentrated under vacuum to afford thetitle compound (82) (0.56 g, 83%) as an oil, which was used immediatelyin the next step without further purification. ¹H-NMR (300 MHz, CDCl₃):δ 4.50 (s, 2H), 4.10 (t, J=6.6 Hz, 2H), 1.72-1.64 (m, 2H), 1.32 (s, 6H),0.95 (t, J=7.2 Hz, 3H).

Example 83 Synthesis of Butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (83) Step 1: Synthesis ofButyl 3-hydroxy-2,2-dimethylpropanoate (83a)

A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) wascharged and 1-butanol (15 mL) and conc. H₂SO₄ (70 μL, 1.3 mmol) in a 20mL-microwave vial was stirred at room temperature then heated in amicrowave at 80° C. for 2 h, then stirred at room temperature overnight.When the desired product was identified by TLC (EtOAc/hexanes; 3:7) themixture was concentrated under vacuum (40° C.; co-evaporated withtoluene×3) and diluted with EtOAc (80 mL) and H₂O (30 mL). The organiclayer was washed with H₂O (twice), and brine, then dried (Na₂SO₄),filtered and concentrated to give the product (83a) (1.24 g, 81%) as anoil. The material was used next step directly without purification.¹H-NMR (300 MHz, CDCl₃): δ 4.11 (t, J=6.5 Hz, 2H), 3.55 (s, 2H), 2.42(br. s, 1H), 1.65-1.58 (m, 2H), 1.43-1.35 (m, 2H), 1.19 (s, 6H), 0.94(t, J=7.5 Hz, 3H).

Step 2: Synthesis of Butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (83)

A solution of freshly distilled sulfuryl chloride (198 μL, 2.7 mmol) inEt₂O (1.0 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of propyl 3-hydroxy-2,2-dimethylpropanoate (83a) (0.47 g, 2.7mmol) and pyridine (219 μL, 2.7 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 5 min. The flask wasrinsed with Et₂O (3×1 mL), which was added to the reaction mixture. Themixture was stirred at −78° C. for 5 min and then allowed to warm toroom temperature and stirred for 1 h. The mixture was filtered, and thefiltrate was concentrated under vacuum to afford the title compound (83)(0.52 g, 72%) as an oil, which was used immediately in the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.50 (s, 2H),4.14 (t, J=6.8 Hz, 2H), 1.66-1.59 (m, 2H), 1.43-1.35 (m, 2H), 1.32 (s,6H), 0.94 (t, J=7.4 Hz, 3H).

Example 84 Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylPivalate (84)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl Pivalate (84a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (47a) (0.86 g, 7.3mmol) in DCM (9 mL) at ca. 0° C. (ice bath) under an argon atmosphere,was added trimethylacetyl chloride (0.89 mL, 7.3 mmol), Et₃N (1.17 mL,14.5 mmol), and N,N-4-dimethylaminopyridine (catalytic amount). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The mixture was quenched by theaddition of 1N HCl (50 mL). The organic and aqueous layers werepartitioned and the aqueous layer was extracted with DCM (twice). Thecombined organic layers were washed with saturated NaHCO₃ and brine,then dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 3:7) as eluent to give the desired product (84a) (0.42 g, 28%).¹H-NMR (300 MHz, CDCl₃): δ 4.13 (t, J=7.1 Hz, 2H), 3.35 (s, 2H), 1.61(q, J=6.9 Hz, 2H), 1.19 (s, 9H), 0.93 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl Pivalate(84)

A solution of freshly distilled sulfuryl chloride (153 μL, 2.1 mmol) inEt₂O (4.5 mL) was cooled to −78° C. under an argon atmosphere. Asolution of 4-hydroxy-3,3-dimethylbutyl pivalate (84a) (0.42 g, 2.1mmol) and pyridine (203 μL, 2.5 mmol) in Et₂O (3 mL) was added dropwiseto the sulfuryl chloride solution over the course of 60 min. The mixturewas allowed to warm to room temperature and stirred for 30 min. Themixture was filtered, and the filtrate was concentrated under vacuum toafford the title compound (84) as an oil, which was used immediately inthe next step without further purification. ¹H-NMR (300 MHz, CDCl₃): δ4.23 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 1.71 (t, J=6.6 Hz, 2H), 1.19 (s,9H), 1.08 (s, 6H).

Example 85 Synthesis of Ethyl2-(((chlorosulfonyl)oxy)methyl)-2-ethylbutanoate (85)

A solution of freshly distilled sulfuryl chloride (126 μL, 1.7 mmol) inEt₂O (3.2 mL) was cooled to −78° C. under an argon atmosphere. Asolution of ethyl 2-ethyl-2-(hydroxymethyl)butanoate (ex-enamine) (0.30g, 1.7 mmol) and pyridine (153 μL, 1.9 mmol) in Et₂O (2.1 mL) was addeddropwise to the sulfuryl chloride solution over the course of 60 min.The mixture was allowed to warm to room temperature and stirred for 30min. The mixture was re-cooled to −78° C. and sulfuryl chloride (20 μL)was added, and the reaction allowed to warm to room temperature andstirred for a further 30 min. Et₂O (5 mL) was added and the mixturestirred for 5 min, then filtered, and the filtrate was concentratedunder vacuum to afford the title compound (85), which was usedimmediately in the next step without further purification. ¹H-NMR (300MHz, CDCl₃): δ 4.62 (s, 2H), 4.21 (q, J=7.3 Hz, 2H), 1.78-1.58 (m, 4H),1.28 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.7 Hz, 6H).

Example 86 Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethylbenzoate (86)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethylbenzoate(86a)

To a stirred solution of 2,2-dimethylbutane-1,4-iol (47a) (0.84 g, 7.1mmol) in DCM (9 mL) at ca. 0° C. (ice bath) under an argon atmosphere,was added 2,6-dimethylbenzoyl chloride (1.0 g, 5.9 mmol), pyridine (0.96mL, 11.9 mmol), and N,N-4-dimethylaminopyridine (catalytic amount). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The mixture was quenched by theaddition of 1N HCl (50 mL). The organic and aqueous layers werepartitioned and the aqueous layer was extracted with DCM (twice). Thecombined organic layers were washed with saturated NaHCO₃, and thendried (Na₂SO₄), and concentrated under vacuum. The residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 3:7)as eluent to give the desired product (86a) (0.42 g, 28%). ¹H-NMR (300MHz, CDCl₃): δ 7.18 (t, J=7.6 Hz, 1H), 7.04-7.01 (m, 2H), 4.41 (t, J=7.6Hz, 2H), 3.37 (s, 2H), 2.31 (s, 6H), 1.76 (t, J=7.5 Hz, 2H), 0.97 (s,6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethylbenzoate (86)

A solution of freshly distilled sulfuryl chloride (122 μL, 1.7 mmol) inEt₂O (1.0 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethylbenzoate (86a) (0.42g, 1.7 mmol) and pyridine (136 μL, 1.7 mmol) in Et₂O (1.5 mL) was addeddropwise to the sulfuryl chloride solution over the course of 15 min.The flask was rinsed with Et₂O (2×20 mL), and the rinse was added to thereaction mixture. The mixture was stirred at −78° C. for 10 min thenallowed to warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (86) as an oil, which was used immediately in the nextstep without further purification (not pure). ¹H-NMR (300 MHz, CDCl₃): δ7.19 (t, J=7.7 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.41 (t, J=7.4 Hz, 2H),4.23 (s, 2H), 2.31 (s, 6H), 1.84 (t, J=6.9 Hz, 2H), 1.11 (s, 6H).

Example 87 Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyladamantane-1-carboxylate (87)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyladamantane-1-carboxylate (87a).

To a stirred solution of 2,2-dimethylbutane-1,4-diol (45a) (0.72 g, 6.1mmol) in DCM (20 mL) at ca. 0° C. (ice bath) under an atmosphere ofargon, was added 1-adamantane-carbonyl chloride (1.1 g, 10.1 mmol),pyridine (0.82 mL, 10.1 mmol), and N,N-4-dimethylaminopyridine (0.03 g,0.3 mmol). The reaction mixture was allowed to gradually warm to roomtemperature and the mixture was stirred overnight. The mixture wasquenched by the addition of 1N HCl. The organic and aqueous layers werepartitioned, and the aqueous layer was extracted with DCM (twice). Thecombined organic layers were washed with saturated NaHCO₃ and brine, andthen dried (MgSO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 1:1) as eluent to give the desired product (87a) (0.49 g, 35%).¹H-NMR (300 MHz, CDCl₃): δ 4.14-4.09 (m, 2H), 3.34 (s, 2H), 2.00 (m,3H), 1.90-1.86 (m, 6H), 1.75-1.59 (m, 6H), 1.59 (t, J=7.1 Hz, 2H), 0.92(s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyladamantane-1-carboxylate (87)

A solution of freshly distilled sulfuryl chloride (127 μL, 1.7 mmol) inEt₂O (1.2 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl adamantane-1-carboxylate (87a)(0.48 g, 1.7 mmol) and pyridine (141 μL, 1.7 mmol) in Et₂O (1.7 mL) wasadded dropwise to the sulfuryl chloride solution over the course of 15min. The flask was rinsed with Et₂O (2×20 mL), and the rinse was addedto the reaction mixture. The mixture was stirred at −78° C. for 10 minand then allowed to warm to room temperature and stirred for 1 h. Themixture was filtered, and the filtrate was concentrated under vacuum toafford the title compound (87) as an oil, which was used immediately inthe next step without further purification (not pure). ¹H-NMR (300 MHz,CDCl₃): δ 4.25 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 2.01 (m, 3H), 1.90-1.85(m, 6H), 1.73-1.69 (m, 8H), 1.08 (s, 6H).

Example 88 Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethoxybenzoate (88)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethoxybenzoate(88a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (47a) (1.85 g, 15.7mmol) in DCM (28 mL) at ca. 0° C. (ice bath) under an atmosphere ofargon, was added 2,6-dimethoxybenzoyl chloride (80%; 3.93 g, 15.7 mmol),Et₃N (2.5 mL, 31.3 mmol), and N,N-4-dimethylaminopyridine (catalyticamount). The reaction mixture was allowed to gradually warm to roomtemperature and the mixture was stirred overnight. The mixture wasconcentrated under vacuum and suspended in EtOAc, and then filtered andthe filter cake washed with EtOAc. The filtrate was concentrated undervacuum and the residue purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 2:3) as eluent to give the desired product(88a) (ca. 80% purity; 0.92 g). ¹H-NMR (300 MHz, CDCl₃): δ 7.29-7.26 (m,1H), 6.57-6.53 (m, 3H), 4.43-4.39 (m, 2H), 3.83 (s, 6H), 3.36 (s, 2H),1.74 (t, J=6.5 Hz, 2H), 0.95 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethoxybenzoate (88)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.7 mmol) inEt₂O (1.9 mL) was cooled to −78° C. under an argon atmosphere. Asolution of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethoxybenzoate (88a) (ca.80% purity; 0.97 g, 2.7 mmol) and pyridine (222 μL, 2.7 mmol) in Et₂O(2.7 mL) was added dropwise to the sulfuryl chloride solution over thecourse of 15 min. The flask was rinsed with Et₂O (2×20 mL), and therinse was added to the reaction mixture. The mixture was stirred at −78°C. for 10 min then allowed to warm to room temperature and stirred for 1h. The mixture was filtered, and the filtrate was concentrated undervacuum to afford the title compound (88) as an oil, which was usedimmediately in the next step without further purification (not pure).

Example 89 Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentylBenzoate (89)

Step 1: Synthesis of 5-hydroxy-4,4-dimethylpentyl benzoate (89a)

To a stirred solution of 2,2-dimethylpentane-1,5-diol (J. Org. Chem.2010, 75, 1892-1897; PCT International Publication No. WO 2002092606)(1.55 g, 11.7 mmol) in DCM (20 mL) at ca. 0° C. (ice bath) under anargon atmosphere, was added benzoyl chloride (1.5 mL, 12.9 mmol). Thereaction mixture was stirred at room temperature for 2.5 h andconcentrated under vacuum. EtOAc was added to the residue and themixture was stirred. The filtrate was concentrated under the residuepurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 1:4) as eluent to give the product (89a) (1.38 g, 50%) as an oil.¹H-NMR (300 MHz, CDCl₃): δ 8.04 (d, J=6.9 Hz, 2H), 7.56 (t, J=7.5 Hz,1H), 7.44 (t, J=7.5 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 3.36 (s, 2H),1.81-1.71 (m, 2H), 1.42-1.36 (m, 2H), 0.92 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl Benzoate(89)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.7 mmol) inEt₂O (1.9 mL) was cooled to −78° C. under an argon atmosphere. Asolution of 4-hydroxy-3,3-dimethylpentyl benzoate (89a) (0.76 g, 3.2mmol) and pyridine (218 μL, 2.7 mmol) in Et₂O (2.7 mL) was addeddropwise to the sulfuryl chloride solution over the course of 15 min.The flask was rinsed with Et₂O (2×20 mL), and the rinse was added to thereaction mixture. The mixture was stirred at −78° C. for 10 min thenallowed to warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (89) as an oil, which was used immediately in the nextstep without further purification (not pure). ¹H-NMR (300 MHz, CDCl₃): δ8.04 (d, J=7.5 Hz, 2H), 7.57-7.55 (m, 1H), 7.48-7.33 (m, 1H), 4.35-4.29(m, 2H), 4.23 (s, 2H), 1.81-1.74 (m, 2H), 1.53-1.21 (m, 2H), 1.06 (s,6H).

Example 90 Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethoxybenzoate (90)

Step 1: Synthesis of 5-hydroxy-4,4-dimethylpentyl 2,6-dimethoxybenzoate(90a)

To a stirred solution of 2,2-dimethylpentane-1,5-diol (1.5 g, 11.3 mmol)in pyridine (8.3 mL) at 0° C. under an argon atmosphere was added2,6-dimethoxybenzoyl chloride (80%; 1.4 g, 5.6 mmol) in one portion. Thereaction mixture was allowed to warm to room temperature and for 3 h.The reaction mixture was concentrated to dryness and EtOAc was added.The mixture was filtered and the filtrate was concentrated under vacuum.The residue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 3:7) as eluent to give the product (90a) (0.65 g,39%) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 7.31-7.26 (m, 2H), 6.55 (d,J=8.1 Hz, 2H), 4.33 (t, J=6.2 Hz, 2H), 3.82 (s, 6H), 3.33 (s, 2H),1.77-1.67 (m, 2H), 1.41-1.35 (m, 2H), 0.92 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethoxybenzoate (90)

A solution of freshly distilled sulfuryl chloride (0.16 mL, 2.2 mmol) inEt₂O was cooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-4,4-dimethylpentyl 2,6-dimethoxybenzoate (90a) (0.65 g, 2.2mmol) and pyridine (177 μL, 2.2 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 15 min. The flask wasrinsed with Et₂O (2×20 mL), and the rinse was added to the reactionmixture. The mixture was stirred at −78° C. for 10 min and then allowedto warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (90) as an oil, which was used immediately in the nextstep without further purification (not pure). ¹H-NMR (300 MHz, CDCl₃): δ7.32-7.26 (m, 1H), 6.56 (d, J=8.7 Hz, 2H), 4.34 (t, J=6.2 Hz, 2H), 4.21(s, 2H), 3.81 (s, 6H), 1.77-1.71 (m, 2H), 1.52-1.46 (m, 2H), 1.03 (s,6H).

Example 91 Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethylbenzoate (91)

Step 1: Synthesis of 5-hydroxy-3,3-dimethylpentyl 2,6-dimethylbenzoate(91a)

To a stirred solution of 2,2-dimethylpentane-1,5-diol (1.1 g, 8.3 mmol)in pyridine (8.3 mL) at 0° C. under an argon atmosphere was added2,6-dimethylbenzoyl chloride in one portion. The reaction mixture wasallowed to warm to room temperature for 3 h. The reaction wasconcentrated to dryness and EtOAc was added. The mixture was filteredand the filtrate was concentrated under vacuum. The residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 1:4)as eluent to give the product (91a) (0.44 g, 25%) as an oil. ¹H-NMR (300MHz, CDCl₃): δ 7.18 (t, J=7.7 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.32 (t,J=6.3 Hz, 2H), 3.34 (s, 2H), 2.32 (s, 6H), 1.78-1.68 (m, 2H), 1.40-1.34(m, 2H), 0.90 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethylbenzoate (91)

A solution of freshly distilled sulfuryl chloride (122 μL, 1.7 mmol) inEt₂O was cooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-4,4-dimethylpentyl 2,6-dimethylbenzoate (91a) (0.44 g, 1.7mmol) and pyridine (135 μL, 1.7 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 15 min. The flask wasrinsed with Et₂O (2×20 mL), and the rinse was added to the reactionmixture. The mixture was stirred at −78° C. for 10 min and then allowedto warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (91), which was used immediately in the next step withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃): δ 7.19 (t, J=7.5 Hz, 1H),7.03 (d, J=7.5 Hz, 2H), 4.33 (t, J=6.2 Hz, 2H), 4.20 (s, 2H), 2.32 (s,6H), 1.81-1.71 (m, 2H), 1.51-1.45 (m, 2H), 1.04 (s, 6H).

Example 92 Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2-methylbenzoate (92)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2-methylbenzoate (92a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (45a) (0.80 g, 6.8mmol) in pyridine (5 mL) at ca. 0° C. (ice bath) under an argonatmosphere, was added toluoyl chloride (0.89 mL, 6.8 mmol) dropwise. Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred for 4 h. The mixture was concentrated undervacuum and suspended in EtOAc, and then filtered and the filter cakewashed with EtOAc. The filtrate was concentrated under vacuum and theresidue purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 3:7) as eluent to give the desired product (92a)(0.7 g, 44%). ¹H-NMR (300 MHz, CDCl₃): δ 7.88 (d, J=8.4 Hz, 1H), 7.40(t, J=7.1 Hz, 1H), 7.26-7.24 (m, 2H), 4.38 (t, J=7.3 Hz, 2H), 3.41 (s,3H), 2.60 (s, 3H), 1.78 (t, J=7.5 Hz, 2H), 0.98 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2-methylbenzoate (92)

A solution of freshly distilled sulfuryl chloride (96 μL, 1.3 mmol) inEt₂O (0.8 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl 2-methylbenzoate (92a) (0.31 g,1.3 mmol) and pyridine (106 μL, 1.3 mmol) in Et₂O (1.1 mL) was addeddropwise to the sulfuryl chloride solution over the course of 15 min.The flask was rinsed with Et₂O (2×20 mL), which was added to thereaction mixture. The mixture was stirred at −78° C. for 10 min thenallowed to warm to room temperature and stirred for 30 min. The mixturewas filtered, and the product (92) was used immediately in the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl₃): δ 7.89 (d, J=8.1Hz, 1H), 7.41-7.39 (m, 1H), 7.26-7.25 (m, 2H), 4.41-4.35 (m, 2H), 4.28(s, 2H), 2.61 (s, 3H), 1.87 (t, J=7.2 Hz, 2H), 1.13 (s, 6H).

Example 93 Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl3-chloro-2,6-dimethoxybenzoate (93)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl2,6-dimethoxybenzoate (93a).

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (67a) (0.7g, 4.8 mmol) in DCM (20 mL) at 0° C. under an atmosphere of argon wasadded 2,6-dimethoxybenzoyl chloride (80%; 0.55 g, 2.2 mmol), pyridine(0.36 mL, 4.4 mmol) and N,N-4-dimethylaminopyridine (0.05 g, 0.4 mmol).The mixture was allowed to warm to room temperature and stirred at roomtemperature overnight. The mixture was cooled to 0° C. and the reactionwas quenched by the addition of 1N HCl (15 mL), and then extracted withDCM (twice). The combined organic layers were washed with sat. sodiumbicarbonate and brine, then dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 3:2) as eluent to give the product (93a) asan oil. ¹H-NMR (300 MHz, CDCl₃): δ 7.29 (t, J=8.4 Hz, 1H), 6.56 (d,J=8.1 Hz, 2H), 4.24 (s, 2H), 3.81 (s, 6H), 3.49 (s, 2H), 0.98 (s, 6H),0.92 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl3-chloro-2,6-dimethoxybenzoate (93)

Pyridine (0.15 mL, 1.8 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl propionate (93a) (0.30 g, 1.5 mmol)and Et₂O (10 mL) under an atmosphere of argon. The solution was cooledto −78° C. and sulfuryl chloride (0.15 mL, 1.8 mmol) in Et₂O (3 mL) wasslowly added at −78° C. The mixture was stirred at −78° C. for 1 h andthen warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the title compound (93) as an oil,that was used directly in the next step without further purification(yield assumed quantitative).

Example 94 Synthesis of2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl Dibenzoate (94)

Step 1: Synthesis of 2-(hydroxymethyl)-2-methylpropane-1,3-diylDibenzoate (91a)

Benzoyl chloride (2.46 mL, 20.0 mmol) was added dropwise to a mixture of2-(hydroxymethyl)-2-methylpropane-1,3-diol (1.2 g, 10.0 mmol), pyridine(2.02 mL, 25.0 mmol), and N,N-4-dimethylaminopyridine (0.06 g, 0.4 mmol)in DCM (30 mL) at room temperature. After stirring at room temperatureovernight, the organic phase was washed with 1 M HCl, water, and brine,dried (MgSO₄), and concentrated under vacuum. The residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 2:3)as eluent to give the product (94a) (1.3 g, 40%) as an oil. ¹H-NMR (300MHz, CDCl₃): δ 8.06-8.02 (m, 4H), 7.62-7.56 (m, 2H), 7.49-7.42 (m, 4H),4.39 (s, 2H), 4.38 (s, 2H), 3.59 (s, 2H), 1.16 (s, 3H).

Step 2: Synthesis of2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl dibenzoate (94)

A solution of freshly distilled sulfuryl chloride (0.3 mL, 3.7 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 2-(hydroxymethyl)-2-methylpropane-1,3-diyl dibenzoate (94a)(800 mg, 2.4 mmol) and pyridine (0.32 mL, 3.9 mmol) in Et₂O (5 mL) wasadded dropwise to the sulfuryl chloride solution over the course of 5min. The flask was rinsed with Et₂O (3 mL), which was also added to themixture. The mixture was stirred at −78° C. for 1 h, and then allowed towarm to room temperature. The precipitate was filtered (quickly) and thefilter cake rinsed with Et₂O (12 mL). The filtrate was concentratedunder vacuum at room temperature to afford the title compound (94) as anoil which was used immediately in the next step without furtherpurification.

Example 95 Synthesis of2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl Diacetate (95)

Step 1: Synthesis of 2-(hydroxymethyl)-2-methylpropane-1,3-diylDiacetate (95a)

Acetic anhydride (3.46 mL, 36.6 mmol) was added dropwise to a mixture of2-(hydroxymethyl)-2-methylpropane-1,3-diol (2.2 g, 18.0 mmol), pyridine(12 mL, 25.0 mmol), and N,N-4-dimethylaminopyridine (0.05 g) at roomtemperature. After stirring at room temperature overnight, the mixturewas concentrated under vacuum. The mixture was suspended in EtOAc (100mL), and H₂O (20 mL) was slowly added at 0° C. The aqueous and organiclayers were partitioned, and the organic layer was washed with andbrine, dried (Na₂SO₄), then concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 3:2) as eluent to give the product (95a) (1.0 g, 26%). ¹H-NMR (300MHz, CDCl₃): δ 4.02 (s, 4H), 3.41 (s, 2H), 2.08 (s, 6H), 0.96 (s, 3H).

Step 2: Synthesis of2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl diacetate (95)

A solution of freshly distilled sulfuryl chloride (0.33 mL, 4.0 mmol) inEt₂O (4 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 2-(hydroxymethyl)-2-methylpropane-1,3-diyl diacetate (95a)(550 mg, 2.7 mmol) and pyridine (0.35 mL, 4.3 mmol) in Et₂O (4 mL) wasadded dropwise to the sulfuryl chloride solution over the course of 5min. The flask was rinsed with Et₂O (5 mL), which was also added to themixture. The mixture was stirred at −78° C. for 1 h, then allowed towarm to room temperature. The precipitate was filtered (quickly) and thefilter cake rinsed with Et₂O (12 mL). The filtrate was concentratedunder vacuum at room temperature to afford the title compound (95) as anoil which was used immediately for the next step without furtherpurification.

Example 96 Synthesis of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate(96)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl2,6-dimethoxybenzoate (96a)

To a stirred solution of 2,2,4,4-tetramethylpentane-1,5-diol (64c) (0.64g, 4.0 mmol) and pyridine (0.32 mL, 4.0 mmol) in DCM (27 mL) was added2,6-dimethoxybenzoyl chloride (80%; 1.0 g, 4.0 mmol) in DCM (10 mL)dropwise over the course of 30 min at 0° C. (ice bath) under anatmosphere of argon. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was diluted with H₂O (30mL), and the layers were separated. The aqueous layer was extracted withDCM (2×30 mL), and the combined organic layers were washed with brine(30 mL), dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 2:98) as eluent to give the product (96a) (927 mg, 71%) as an oil.The compound was contaminated, presumably with the diacylated byproduct.The material was used in the next step without further purification.

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethoxybenzoate (96)

A solution of sulfuryl chloride (0.21 mL, 2.8 mmol) in Et₂O (13 mL) wascooled to −78° C. under an argon atmosphere. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate (96a) (921 mg,2.8 mmol) and pyridine (0.23 mL, 2.8 mmol) in Et₂O (13 mL) was addeddropwise to the sulfuryl chloride solution over the course of 10 min.The mixture was stirred at −78° C. for 5 h. The mixture was filtered andthe filtrate stored to give a solution of the product (96) in Et₂O (ca.20 mL). The yield was assumed to be quantitative. This mixture was usedin the next step without further purification.

Example 97 Synthesis of R/S-ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylbutanoate (97)

A solution of freshly distilled sulfuryl chloride (148 μL, 2.0 mmol) inEt₂O (0.2 mL) was cooled to −78° C. under an argon atmosphere. Asolution of ethyl 3-hydroxy-2,2-dimethylbutanoate (prepared according toJ. Med. Chem. 1987, 30, 366-374 and Ad. Synth. Catal. 2009, 351,3128-3132) (324 mg, 2.0 mmol) and pyridine (164 μL, 2.0 mmol) in Et₂O(0.2 mL) was added dropwise to the sulfuryl chloride solution over thecourse of 15 min. The flask was rinsed with Et₂O (2×20 mL), which wasadded to the reaction mixture. The mixture was stirred at −78° C. for 30min. The mixture was filtered and the product (97a) was used directly inthe next step with an assumed quantitative yield. ¹H-NMR (300 MHz,CDCl₃): δ 5.34-5.29 (m, 1H), 4.22-4.14 (m, 2H), 1.55-1.52 (m, 3H),1.35-1.08 (m, 9H).

Example 98 Synthesis of(3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl Sulfochloridate (98)

Step 1: Synthesis of 3,5,5-trimethyldihydrofuran-2(3H)-one (98a)

5,5-Dimethyldihydrofuran-2(3H)-one (4.7 g, 41.2 mmol) was dissolved inTHF (94 mL) and the mixture was cooled to −78° C. under an atmosphere ofargon. A solution of lithium diisopropylamide, 2.0 M solution in THF(22.6 mL, 45.2 mmol) was added dropwise over 10 min. The reaction wasstirred at −78° C. for 2 h, and then neat MeI (2.6 mL, 41.6 mmol) wasadded to the reaction over 5 min. The reaction was stirred at −78° C.for 45 min, and then the mixture was allowed to warm to room temperatureand stirred for 16 h. The reaction was quenched with saturated NH₄Cl (25mL) and the mixture concentrated to remove THF. The aqueous residue wasdiluted with H₂O to dissolve solid and then extracted with ethyl acetate(3×40 mL). The combined organic layer was concentrated under vacuum, andthe residue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 2:3) as eluent to provide a liquid whichsolidified on standing. This solid was purified further via Kugelrohrdistillation to give the product (98a) (3.2 g) as an oil. ¹H-NMR (300MHz, CDCl₃): δ 2.78-2.87 (m, 1H), 2.33 (dd, J=9.3, 12.3 Hz, 1H), 1.71(t, J=12.3 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H), 1.29 (d, J=6.9 Hz, 3H).

Step 2: Synthesis of3-((benzyloxy)methyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (98b)

3,5,5-Trimethyldihydrofuran-2(3H)-one (98a) (3.2 g, 25.0 mmol) wasdissolved in THF (60 mL) and the mixture was cooled to −78° C. under anatmosphere of argon. A solution of lithium diisopropylamide, 2.0 M inTHF (13.7 mL, 27.5 mmol) was added dropwise over 10 min. The mixture wasstirred at −78° C. for 30 min, then neat benzyl chloromethyl ether (90%;4.2 mL, 27.5 mmol) was added over 5 min. The mixture was allowed to warmto room temperature and was stirred for 16 h. Saturated NH₄Cl (10 mL)and H₂O (10 mL) was added and the solvent was removed under vacuum. Theresidue was extracted with EtOAc (2×75 mL) and the combined organiclayers were washed with brine (2×75 mL), dried (Na₂SO₄), filtered andconcentrated under vacuum (5.8 g). The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 2:3) as eluentto give the product (2.27 g) and impure fractions (1.35 g). The impurefractions were re-purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 1:4) as eluent to give additional pure product(98b) (1.39 g). The product (3.66 g) was an oil. ¹H-NMR (300 MHz,CDCl₃): δ 7.28-7.34 (m, 5H), 4.62 (dd, J=11.7, 35.1 Hz, 2H), 3.61 (d,J=11.7 Hz, 1H), 3.32 (d, J=11.7 Hz, 1H), 2.48 (d, J=12.9 Hz, 1H), 1.89(d, J=12.9 Hz, 1H), 1.45 (d, J=6.9 Hz, 6H), 1.26 (s, 3H).

Step 3: Synthesis of3-(hydroxymethyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (98c)

3-((Benzyloxy)methyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (98b) (1.8g, 7.2 mmol) was dissolved in 2-propanol (60 mL) and the solution wasdegassed with argon. Solid 10.0% palladium on carbon (0.31 g, 0.3 mmol)was added to the flask. The flask was sealed and vacuum degassed, andthen back flushed with hydrogen (3 times). The reaction was stirred for6 h. The suspension was filtered through Celite R and the filter cakewashed with 2-propanol (15 mL). The filtrate was concentrated undervacuum to provide the product (98c) as a crude oil. ¹H-NMR (300 MHz,CDCl₃): δ 3.75 (dd, J=6.9, 11.1 Hz, 1H), 3.51 (dd, J=5.7, 11.1 Hz, 1H),2.33 (d, J=12.9 Hz, 1H), 2.23 (t, J=6 Hz, 1H), 1.94 (d, J=12.9 Hz, 1H),1.48 (d, J=6.9 Hz, 6H), 1.32 (s, 3H).

Step 4: Synthesis of (3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methylSulfochloridate (98)

A solution of 3-(hydroxymethyl)-3,5,5-trimethyldihydrofuran-2(3H)-one(98c) (0.50 g, 3.2 mmol) and pyridine (0.28 mL, 3.5 mmol) in Et₂O (10mL) was cooled to −78° C. under an atmosphere of argon. Neat sulfurylchloride (0.28 mL, 3.5 mmol) was added dropwise to the above solutionvia syringe. The mixture was stirred at −78° C. for 10 min, then theflask was warmed to room temperature and stirred for 1 h (monitored byTLC 30% EA/hexanes). A precipitate formed to give a thick suspension.The suspension was filtered through a 0.45-μM Teflon® filter and thefilter cake rinsed with fresh Et₂O (2×5 mL). An aliquot (0.5 mL) wastaken and concentrated and an NMR was obtained for the mixture. Theremaining solution containing the product (98) was used directly in thenext step. ¹H-NMR (300 MHz, CDCl₃): δ 4.60 (d, J=9.3 Hz, 1H), 4.36 (d,J=9.3 Hz, 1H), 2.37 (d, J=14.1 Hz, 1H), 2.09 (d, J=13.5 Hz, 1H), 1.51(d, J=8.4 Hz, 6H), 1.44 (s, 3H).

Example 99 Aztreonam Release from Prodrug

U.S. application Ser. No. 15/934,497, filed on Mar. 23, 2018, and due toissue as U.S. Pat. No. 10,085,999, discloses derivatives of theβ-lactamase inhibitor, avibactam, having promoieties similar to thosedisclosed herein. Several of the avibactam derivatives exhibited oralbioavailability of the parent drug, avibactam, following oraladministration to rats, dogs, and monkeys. Based on these results, itcan be expected that the derivatives of aztreonam disclosed herein,including the compounds of Formula (1)-(4) will adhere to the samerelease mechanism and will exhibit oral bioavailability of the parentdrug, aztreonam.

Example 100 Oral Bioavailability

A pharmacokinetic (PK) study can be performed in three maleSprague-Dawley (SD) rats following intravenous (IV) and oral (PO)administration of aztreonam at 2 mg/kg and test compounds at 10 mg/kg,respectively and aztreonam measured in plasma.

Aztreonam is dissolved in phosphate buffered saline (PBS) (pH 7.5) at0.4 mg/mL for intravenous (IV) injection. Compounds for oraladministration are formulated in 10% ethanol/40% polyethylene glycol(PEG) 400/50% water for injection (WFI) (pH 6.5) at 1 mg/mL. The dosingvolumes are 5 mL/kg for IV and 10 mL/kg for PO. All aspects of this workincluding housing, experimentation, and animal disposal are performed ingeneral accordance with the “Guide for the Care and Use of LaboratoryAnimals: Eighth Edition” (National Academies Press, Washington, D.C.,2011); and Suckow et al., Ed. The Laboratory Rat. 2nd Edition. AcademicPress. New York. 2005. Animals have access to standard lab diet andautoclaved tap water ad libitum.

Blood aliquots (300 μL to 400 μL) are collected from jugularvein-catheterized rats into tubes coated with lithium heparin at varioustimes. The tubes are mixed gently and kept on ice and then centrifugedat 2,500 rpm for 15 min at 4° C., within 1 h after collection. Foranimals in the control groups, blood is collected by cardiac punctureand the plasma is harvested and kept frozen at −70° C. until furtheranalysis. Beaudoin et al., Bioanalytical method validation for thesimultaneous determination of ceftazidime and aztreonam in rat plasma.Bioanalysis. 2016 8:111-22.

Plasma samples are processed using acetonitrile precipitation andanalyzed by LC-MS/MS. A plasma calibration curve is generated withaliquots of drug-free plasma are spiked with the test substance at thespecified concentration levels. The spiked plasma samples are processedtogether with the unknown plasma samples using the same procedure. Theprocessed plasma samples can be stored at −70° C. until receivingLC-MS/MS analysis, at which time peak areas are recorded, and theconcentrations of the test substance in the unknown plasma samples aredetermined using the respective calibration curve. The reportable linearrange of the assay is determined, along with the lower limit ofquantitation (LLQ). Plots of plasma concentration of compound versustime are constructed. The pharmacokinetic parameters of compound afterIV and PO dosing (AUC_(last), AUC_(INF), T_(1/2), T_(max), and C_(max))are obtained from the non-compartmental analysis (NCA) of the plasmadata using WinNonlin. WinNonlin® Certara L.P. Pharsight, St. Louis, Mo.

Example 101 Minimum Inhibitory Concentration

Minimum inhibitor concentration (MIC) values of the monobactamantibiotics are determined by broth microdilution susceptibility testingconducted in accordance with guidelines from the Clinical and LaboratoryStandards Institute (Clinical and Laboratory Standards Institute (CLSI).Methods for Dilution Antimicrobial Susceptibility Tests for BacteriaThat Grow Aerobically; Approved Standard-Tenth Edition. CLSI documentM07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa. 19087-1898USA, 2015; CLSI, Performance Standards for Antimicrobial SusceptibilityTesting: Twenty-Sixth Informational Supplement. CLSI document M100-S26.CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa. 19087 USA, 2016)against a panel of gram-negative bacterial strains. Compounds are storedas dry powder and stored at −20° C. prior to testing. These compoundsand comparative antibiotics are solubilized in the appropriate solventon the day of the assay. All antibiotics are tested using aconcentration, for example, within a range from 0.001 μg/mL to 64 μg/mL.Antibiotics are tested at a constant concentration of, for example, 4μg/mL. Isolates are streaked onto appropriate media and incubatedovernight at 35° C. The MIC values are determined using cation-adjustedMueller Hinton broth (MHBII; BD, Sparks, Md.) in accordance with CLSIguidelines in 96-well format plates. MICs are recorded after 18 hincubation at 35° C. The MIC is read and recorded as the lowestconcentration of antibiotic that inhibits visible growth of theorganism.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein but maybe modified within the scope and equivalents thereof.

What is claimed is:
 1. A compound of Formula (1):

wherein, each R¹ is independently selected from C₁₋₆ alkyl, or each R¹and the geminal carbon atom to which each R¹ is bonded forms a C₃₋₆cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆cycloalkyl ring, or a substituted C₃₋₆ heterocycloalkyl ring; R² isselected from a single bond, C₁₋₆ alkanediyl, C₁₋₆ heteroalkanediyl,C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆ arenediyl, C₅₋₆heteroarenediyl, substituted C₁₋₆ alkanediyl, substituted C₁₋₆heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl, substituted C₅₋₆heterocycloalkanediyl, substituted C₆ arenediyl, and substituted C₅₋₆heteroarenediyl; R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴,—NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴,—C(O)—S—R⁴, —C(O)—NH—R⁴, —O—(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴,—S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆heteroaryl, substituted C₅₋₆ cycloalkyl, substituted C₅₋₆heterocycloalkyl, substituted C₅₋₆ aryl, and substituted C₅₋₆heteroaryl, wherein, R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈heteroalkyl, C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀cycloalkylalkyl, C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈heteroaryl, C₇₋₁₀ arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈alkyl, substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀ cycloalkylalkyl,substituted C₅₋₁₀ heterocycloalkylalkyl, substituted C₆₋₈ aryl,substituted C₅₋₈ heteroaryl, substituted C₇₋₁₀ arylalkyl, andsubstituted C₅₋₁₀ heteroarylalkyl; R⁵ is selected from hydrogen, C₁₋₆alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂ cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈heterocycloalkyl, C₆₋₁₂ heterocycloalkylalkyl, substituted C₁₋₆ alkyl,substituted C₅₋₈ cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl,substituted C₂₋₆ heteroalkyl, substituted C₅₋₈ heterocycloalkyl, andsubstituted C₆₋₁₂ heterocycloalkylalkyl; R⁶ is selected from hydrogen,C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂ cycloalkylalkyl, C₂₋₆ heteroalkyl,C₅₋₈ heterocycloalkyl, C₆₋₁₂ heterocycloalkylalkyl, substituted C₁₋₆alkyl, substituted C₅₋₈ cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl,substituted C₂₋₆ heteroalkyl, substituted C₅₋₈ heterocycloalkyl, andsubstituted C₆₋₁₂ heterocycloalkylalkyl; and R⁷ is selected fromhydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂ cycloalkylalkyl, C₂₋₆heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂ heterocycloalkylalkyl,substituted C₁₋₆ alkyl, substituted C₅₋₈ cycloalkyl, substituted C₆₋₁₂cycloalkylalkyl, substituted C₂₋₆ heteroalkyl, substituted C₅₋₈heterocycloalkyl, and substituted C₆₋₁₂ heterocycloalkylalkyl.
 2. Thecompound of claim 1, wherein each substituent is independently selectedfrom —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl, —COOR,—NR₂, and —CONR₂; wherein each R is independently selected from hydrogenand C₁₋₆ alkyl.
 3. The compound of claim 1, wherein each of R⁵, R₆, andR⁷ is hydrogen.
 4. The compound of claim 1, wherein, each of R⁵ and R⁶is hydrogen; and R⁷ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 5. Thecompound of claim 1, wherein each R¹ is independently C₁₋₆ alkyl, oreach R¹ together with the geminal carbon atom to which each R¹ is bondedform a C₃₋₆ cycloalkyl ring or a substituted C₃₋₆ cycloalkyl ring. 6.The compound of claim 1, wherein R² is selected from a single bond, C₁₋₆alkyl, C₁₋₂ alkanediyl, and substituted C₁₋₂ alkanediyl.
 7. The compoundof claim 1, wherein R³ is selected from —O—C(O)—R⁴, —C(O)—O—R⁴,—S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴, —NH—R⁴, and —CH(—NH₂)(—R⁴); where R⁴ isdefined as for Formula (1), or each R⁴ can be selected from hydrogen andC₁₋₈ alkyl.
 8. The compound of claim 1, wherein R³ is —C(O)—O—R⁴, and R⁴is selected from hydrogen and C₁₋₈ alkyl.
 9. The compound of claim 1,wherein R³ is —C(O)—O—R⁴, wherein R⁴ is selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, C₅₋₇ cycloalkyl, C₅₋₇ heterocycloalkyl, C₆ aryl, C₇₋₉arylalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₆ aryl, and C₇₋₉ arylalkyl.
 10. The compound of claim 1,wherein, R² is a single bond; R³ is C₁₋₃ alkyl; each R¹ together withthe carbon atom to which each R¹ is bonded form a C₄₋₆ heterocycloalkylring or a substituted C₄₋₆ heterocycloalkyl ring each of R⁵ and R⁶ ishydrogen; and R⁷ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 11. Thecompound of claim 1, wherein, each R¹ is methyl; R² is selected from asingle bond, methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—,and 1,2-benzene-diyl; R³ is selected from —O—C(O)—R⁴, —C(O)—O—R⁴,—S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴), wherein R⁴is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇heterocycloalkyl; each of R⁵ and R⁶ is hydrogen; and R⁷ is selected fromhydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 12. The compound of claim 1,wherein, each R¹ is methyl; R² is selected from a single bond,methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and1,2-benzene-diyl; R³ is selected from —C(O)—O—R⁴, wherein R⁴ is selectedfrom C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇heterocycloalkyl; each of R⁵ and R⁶ is hydrogen; and R⁷ is selected fromhydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 13. The compound of claim 1,wherein, each R¹ is methyl; R² is selected from a single bond,methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and1,2-benzene-diyl; R³ is selected from —O—C(O)—R⁴, —C(O)—O—R⁴,—S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴), wherein R⁴is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butylisobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl,cyclopentyl, cyclohexyl, and 2-pyrrolidinyl; each of R⁵ and R⁶ ishydrogen; and R⁷ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 14. Thecompound of claim 1, wherein, each R¹ is methyl; R² is selected from asingle bond, methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—,and 1,2-benzene-diyl; R³ is selected from —C(O)—O—R⁴, wherein R⁴ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butylisobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl,cyclopentyl, cyclohexyl, and 2-pyrrolidinyl; each of R⁵ and R⁶ ishydrogen; and R⁷ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 15. Thecompound of claim 1, wherein, each R¹ is independently C₁₋₃ alkyl; eachR² is a single bond; and each of R⁵, R⁶, and R⁷ is hydrogen.
 16. Thecompound of claim 1, wherein, each R¹ is methyl; R² is a single bond; R³is —(O)—O—R⁴, wherein R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₇₋₁₀ alkylarene, and C₅₋₁₀ heteroalkylcycloalkyl; each ofR⁵ and R⁶ is hydrogen; and R⁷ is selected from hydrogen, C₁₋₆ alkyl,C₁₋₆ heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 17. Thecompound of claim 1, wherein, each R¹ can be selected from C₁₋₆ alkyl;R⁴ can be selected from C₁₋₆ alkyl, C₁₋₆ heteroalkyl, C₅₋₆ cycloalkyl,and C₅₋₆ heterocycloalkyl; each of R⁵ and R⁶ is hydrogen; and R⁷ isselected from hydrogen, C₁₋₆ alkyl, C₁₋₆ heteroalkyl, and4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.
 18. The compound of claim 1,wherein the compound is selected from:2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid;2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid;2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-oxo-3-propoxypropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoicacid; methyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;ethyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;propyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;methyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;ethyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;propyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;methyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;ethyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;propyl3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;a pharmaceutically acceptable salt of any of the foregoing; and acombination of any of the foregoing.
 19. A pharmaceutical compositioncomprising the compound of claim 1 and a pharmaceutically acceptablevehicle.
 20. The pharmaceutical composition of claim 19, wherein thepharmaceutical composition comprises an oral dosage formulation.
 21. Amethod of treating a bacterial infection in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the compound of claim
 1. 21. The method of claim 19,wherein administering comprises orally administering.
 22. The method ofclaim 19, further comprising administering a therapeutically effectiveamount of a β-lactamase inhibitor to the patient.
 23. The method ofclaim 22, wherein the β-lactamase inhibitor comprises a β-lactamaseinhibitor derivative that when administered orally can provide theβ-lactamase inhibitor in the systemic circulation of the patient. 24.The method of claim 21, wherein the bacterial infection is capable ofbeing treated by co-administering a therapeutically effective amount ofaztreonam and a β-lactamase inhibitor.
 25. A method of treating abacterial infection in a patient comprising administering to a patientin need of such treatment a therapeutically effective amount of thepharmaceutical composition of claim
 19. 26. The method of claim 25,wherein administering comprises orally administering.
 27. The method ofclaim 25, further comprising administering a β-lactamase inhibitor tothe patient.
 28. The method of claim 27, wherein the β-lactamaseinhibitor comprises a β-lactamase inhibitor derivative that whenadministered orally can provide the β-lactamase inhibitor in thesystemic circulation of the patient.
 29. A method of synthesizing aderivative of aztreonam comprising: reacting3-amino-2-tert-butoxycarbonylamino-butyric acid benzyl ester and achlorosulfonyloxy ester in the presence of a base to provide thecorresponding((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxyester; hydrogenating the((2R,3R)-4-(benzyloxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutan-2-yl)sulfonyloxyester to provide the corresponding(2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoicacid ester; and cyclizing the(2R,3R)-2-((tert-butoxycarbonyl)amino)-3-((sulfonyloxy)amino)butanoicacid ester in the presence of a cyclization agent to provide thecorresponding β-lactam.
 30. A method of synthesizing a derivative ofaztreonam comprising: reacting tert-butyl(2S,3R)-3-amino-2-(((benzyloxy)carbonyl)-amino)butanoate and achlorosulfonyloxy ester in the presence of a base to provide thecorresponding tert-butyl(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoateester; and following removal of the tert-butyl ester, cyclizing the(2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-((sulfonyloxy)amino)butanoateester in the presence of a cyclization agent to provide thecorresponding β-lactam.